Fused heterocyclic compounds

ABSTRACT

A compound of formula I  
                 
 
wherein m, n, A, B, D, E, G, H, Y, R 1 , R 2 , R 3 , R 4 , R 5 , and R 8 , are described herein.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.60/563,143, filed Apr. 15, 2004, incorporated herein by reference in itsentirety.

FIELD OF THE INVENTION

The present invention provides for fused heterocyclic compounds usefulas inhibitors of potassium channel function (especially inhibitors ofthe K_(v)1 subfamily of voltage gated K⁺ channels, more especiallyinhibitors of K_(v)1.5 (which have been linked to the ultra-rapidlyactivating delayed rectifier K⁺ current I_(Kur)), and/or K_(v)1.3channels, and/or K_(v)1.1 channels) and to pharmaceutical compositionscontaining such compounds. The present invention further provides formethods of using such compounds in the treatment of arrhythmia,I_(Kur)-associated disorders, and other disorders mediated by ionchannel function.

BACKGROUND OF THE INVENTION

The ultra-rapidly activating delayed rectifier K⁺ current (I_(kur)) isbelieved to represent the native counterpart to a cloned potassiumchannel designated K_(v)1.5 and, while present in human atrium, itappears to be absent in human ventricle. Furthermore, because of itsrapidity of activation and limited slow inactivation, I_(kur) isbelieved to contribute significantly to repolarization in human atrium.Consequently, a specific blocker Of I_(kur), that is a compound whichblocks Kv1.5, would overcome the short coming of other compounds byprolonging refractoriness by retarding repolarization in the humanatrium without causing the delays in ventricular reporlarization thatunderlie arrhythmogenic after depolarizations and acquired long QTsyndrome observed during treatment with current Class III antiarrhythmicagents. (Antiarrhythmic agents of Class III are drugs that cause aselective prolongation of the duration of the action potential withoutsignificant cardiac depression.)

Immunoregulatory abnormalities have been shown to exist in a widevariety of autoimmune and chronic inflammatory diseases, includingsystemic lupus erythematosis, chronic rheumatoid arthritis, type I andII diabetes mellitus, inflammatory bowel disease, biliary cirrhosis,uveitis, multiple sclerosis and other disorders such as Crohn's disease,ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis,ichthyosis, Graves ophthalmopathy and asthma. Although the underlyingpathogenesis of each of these conditions may vary, they have in commonthe appearance of a variety of auto-antibodies and self-reactivelymphocytes. Such self-reactivity may be due, in part, to a loss of thehomeostatic controls under which the normal immune system operates.Similarly, following a bone-marrow or an organ transplantation,lymphocytes recognize the foreign tissue antigens and begin to produceimmune mediators which lead to graft rejection or graft-vs-hostrejection.

One end result of an autoimmune or a rejection process is tissuedestruction caused by inflammatory cells and the mediators they release.Anti-inflammatory agents such as NSAID's act principally by blocking theeffect or secretion of these mediators but do nothing to modify theimmunologic basis of the disease. On the other hand, cytotoxic agents,such as cyclophosphamide, act in such a nonspecific fashion in whichboth the normal and autoimmune responses are shut off. Indeed, patientstreated with such nonspecific immunosuppressive agents are as likely tosuccumb to infection as they are to their autoimmune disease.

Cyclosporin A, which was approved by the US FDA in 1983 is currently theleading drug used to prevent rejection of transplanted organs. In 1993,FK-506 (Prograf) was approved by the US FDA for the prevention ofrejection in liver transplantation. Cyclosporin A and FK-506 act byinhibiting the body's immune system from mobilizing its vast arsenal ofnatural protecting agents to reject the transplant's foreign protein. In1994, Cyclosporin A was approved by the US FDA for the treatment ofsevere psoriasis and has been approved by European regulatory agenciesfor the treatment of atopic dermatitis. Though these agents areeffective in fighting transplant rejection, Cyclosporin A and FK-506 areknown to cause several undesirable side effects includingnephrotoxicity, neurotoxicity, and gastrointestinal discomfort.Therefore, a selective immunosuppressant without these side effectsstill remains to be developed. Potassium channel inhibitors as describedhere promise to be the solution to this problem, since inhibitors ofKv1.3, for example, are immunosuppressive. See, Wulff et al., “Potassiumchannels as therapeutic targets for autoimmune disorders,” Curr OpinDrug Discov Devel. 2003 September; 6(5):640-7; Shah et al.,“Immunosuppressive effects of a Kv1.3 inhibitor,” Cell Immunol. 2003February; 221(2):100-6; Hanson et al., “UK-78,282, a novel piperidinecompound that potently blocks the Kv1.3 voltage-gated potassium channeland inhibits human T cell activation,” Br J. Pharmacol. 1999 April;126(8):1707-16.

Inhibitiors of Kv1.5 and other Kv1.x channels stimulate gastrointestinalmotility. Thus, the compounds of the invention are believed to be usefulin treating motility disorders such as reflux esophagitis. See, Frey etal., “Blocking of cloned and native delayed rectifier K channels fromvisceral smooth muscles by phencyclidine,” Neurogastroenterol Motil.2000 December; 12(6):509-16; Hatton et al., “Functional and molecularexpression of a voltage-dependent K(+) channel (Kv1.1) in interstitialcells of Cajal,” J. Physiol. 2001 Jun. 1;533(Pt 2):315-27; Vianna-Jorgeet al., “Shaker-type Kv1 channel blockers increase the peristalticactivity of guinea-pig ileum by stimulating acetylcholine andtachykinins release by the enteric nervous system,” Br J. Pharmacol.2003 January; 138(1):57-62; Koh et al., “Contribution of delayedrectifier potassium currents to the electrical activity of murinecolonic smooth muscle,” J. Physiol. 1999 Mar. 1;515 (Pt 2):475-87.

Inhibitors of Kv1.5 relax pulmonary artery smooth muscle. Thus, thecompounds of the invention are believed to be useful in treatinghypertension and otherwise improving vascular health. See, Davies etal., “Kv channel subunit expression in rat pulmonary arteries,” Lung.2001; 179(3):147-61. Epub 2002 Feb. 04; Pozeg et al., “In vivo genetransfer of the O2-sensitive potassium channel Kv1.5 reduces pulmonaryhypertension and restores hypoxic pulmonary vasoconstriction inchronically hypoxic rats,” Circulation. 2003 Apr. 22; 107(15):2037-44.Epub 2003 Apr. 14.

Inhibitors of Kv1.3 increase insulin sensitivity. Hence, the compoundsof the invention are believed to be useful in treating diabetes. See, Xuet al., “The voltage-gated potassium channel Kv1.3 regulates peripheralinsulin sensitivity,” Proc. Natl. Acad. Sci. U.S.A. 2004 Mar. 2;101(9):3112-7. Epub 2004 Feb. 23 (epublished 2004 Feb. 23); MacDonald etal., “Members of the Kv1 and Kv2 voltage-dependent K(+) channel familiesregulate insulin secretion,” Mol. Endocrinol. 2001 August;15(8):1423-35; MacDonald et al., “Voltage-dependent K(+) channels inpancreatic beta cells: role, regulation and potential as therapeutictargets,” Diabetologia. 2003 August; 46(8):1046-62. Epub 2003 Jun. 27.

Stimulation of Kv1.1 is believed to reduce seizure activity byhyperpolarizing neurons. Thus, the compounds of the invention arebelieved to be useful in treating seizures, including seizuresassociated with epilepsy and other neurological diseases. See, Rho etal., “Developmental seizure susceptibility of kv1.1 potassium channelknockout mice,” Dev Neurosci. 1999 November; 21(3-5):320-7; Coleman etal., “Subunit composition of Kv1 channels in human CNS,” J. Neurochem.1999 August; 73(2):849-58; Lopantsev et al., “Hyperexcitability of CA3pyramidal cells in mice lacking the potassium channel subunit Kv1.1,”Epilepsia. 2003 December; 44(12):1506-12; Wickenden, “Potassium channelsas anti-epileptic drug targets,” Neuropharmacology. 2002 December;43(7):1055-60.

Inhibition of Kv1.x channels improves cognition in animal models. Thus,the compounds of the invention are believed to be useful in improvingcognition and/or treating cognitive disorders. See, Cochran et al.,“Regionally selective alterations in local cerebral glucose utilizationevoked by charybdotoxin, a blocker of central voltage-activatedK+-channels,” Eur J. Neurosci. 2001 November; 14(9):1455-63; Kourrich etal., “Kaliotoxin, a Kv1.1 and Kv1.3 channel blocker, improvesassociative learning in rats,” Behav Brain Res. 2001 Apr. 8;120(1):35-46.

SUMMARY OF THE INVENTION

Provided is a compound of formula I

wherein,

-   n and m are integers such that ring H, including its fusion partner,    is a 5 to 7 membered ring;-   A, B, D and E are —CR⁶═, —CR⁶—, —C(═O)—, —NR⁷—, —N═, —O—, —S—, a    bond, or a double bond, such that ring G, including atoms shared    with its fusion partner, is a 5 to 6 membered ring [the moieties of    A, B, D and E can be inserted into ring G in either orientation],    ring G is a heterocycle wherein at least one ring atom is nitrogen,    and ring G and —C(═O)—, if present, contains at least one    unsaturated bond;-   R¹ is aryl, which ring can be substituted with one or more groups of    the formula —(CH₂)_(p)-(Z¹)_(q)-(CH₂)_(r)-Z²;-   R² is aryl, heteroaryl, cycloalkyl or heterocyclo, which ring    structures can be substituted with one or more groups of the formula    —(CH₂)_(p)-(Z¹)_(q)-(CH₂)_(r)-Z², which substituents may, in one or    more pairs of two, together with the atoms to which they are bonded,    form a carbocyclic, substituted carbocyclic, heterocyclic or    substituted heterocyclic group;-   Y is C(═O)—, —C(═S)—, —C(═NR⁹)—, —C(═NR¹⁰)NR¹¹—, —C(═O, C(═S)—,    —C(═NR¹²)—O—, —SO₂—, —SO₂, or a single bond;-   R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are the same or    different and are independently selected from groups of the formula    —(CH₂)_(p)-(Z¹)_(q)-(CH₂)_(r)-Z²; or    -   R³, R⁴ and R⁵ may, in one or more pairs of two (such as R⁵ and        R³, R² and R³, R³ and R⁴ or R⁴ and R⁵), together with the atoms        to which they are bonded, form a carbocyclic, substituted        carbocyclic, heterocyclic or substituted heterocyclic group; or    -   R⁶ and R⁷ may, in one or more pairs of two, may, together with        the atoms to which they are bonded, form a carbocyclic,        substituted carbocyclic, heterocyclic or substituted        heterocyclic group; or    -   two occurrences of R⁶ (R⁶ and R⁶*) may, together with the atoms        to which they are bonded, form a phenyl, which may be        substituted;-   Z¹ is —CZ³Z⁴-, —O—, —NZ⁵-, —S—, —SO—, —SO₂—, —C(O)—, —C(O)Z⁶-,    —C(O)NZ⁷-, —C(S)—, —C(═NOZ⁸)-, alkyl, substituted alkyl, alkenyl,    substituted alkenyl, alkynyl, substituted alkynyl, carbocyclo,    substituted carbocyclo, aryl, substituted aryl, heterocyclo, or    substituted heterocyclo;-   Z² is hydrogen, —OZ⁹, —OC(O)Z¹⁰, —NZ¹¹-C(O)-Z¹², —NZ¹³-CO₂-Z¹⁴,    —NZ¹⁵(C═O)—NZ¹⁶Z¹⁷, —NZ¹⁸Z¹⁹, —NO₂, halo, —CN, —C(O)Z²⁰, —CO₂Z²¹,    —C(S)Z²², —(C═NOZ²³)Z²⁴, —C(O)NZ²⁵Z²⁶, —C(S)NZ²⁷Z²⁸, —SZ²⁹, —SOZ³⁰,    —SO₂Z³¹, —SO₂NZ³²Z³³, alkyl, substituted alkyl, alkenyl, substituted    alkenyl, alkynyl, substituted alkynyl, carbocyclo, substituted    carbocyclo, aryl, substituted aryl, heterocyclo (such as    heteroaryl), or substituted heterocyclo, or Z² together with Z⁵ may    together with a nitrogen to which they are bonded, form a    carbocyclic, substituted carbocyclic, heterocyclic or substituted    heterocyclic group;-   Z⁵ is hydrogen, —C(O)Z²⁰, —CO₂Z²¹, —C(S)Z²², —(C═NOZ²³)Z²⁴,    —C(O)NZ²⁵Z²⁶, —C(S)NZ²⁷Z²⁸, —SZ²⁹, —SOZ³⁰, —SO₂Z³¹, —SO₂NZ³²Z³³,    alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,    substituted alkynyl, carbocyclo, substituted carbocyclo, aryl,    substituted aryl, heterocyclo (such as heteroaryl), or substituted    heterocyclo or forms a ring with Z² as specified above;-   Z³, Z⁴ Z⁶ Z⁷ Z⁸, Z⁹, z, Z¹, Z², Z³, Z¹⁴, Z¹⁵, Z¹⁶, Z¹⁷, Z¹⁸, Z¹⁹,    Z²⁰, Z²¹, Z²², Z²³, Z²⁴, Z²⁵, Z²⁶, Z²⁷, Z²⁸, Z²⁹, Z³⁰, Z³¹, Z³² and    Z³³ are independently hydrogen, halo, alkyl, substituted alkyl,    alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,    carbocyclo, substituted carbocyclo, aryl, substituted aryl,    heterocyclo, or substituted heterocyclo; or    -   Z³, Z⁴, Z⁶, Z⁷, Z⁸, Z⁹, Z¹⁰, Z¹¹, Z¹², Z¹³, Z¹⁴, Z¹⁵, Z¹⁶, Z¹⁷,        Z¹⁸, Z¹⁹, Z²⁰, Z²¹, Z²², Z²³, Z²⁴, Z²⁵, Z²⁶, Z²⁷, Z²⁸, Z²⁹, Z³⁰,        Z³¹, Z³² and Z³³ (optionally Z³, Z⁴, Z¹¹, Z¹², Z¹³, Z¹⁴, Z¹⁵,        Z¹⁶, Z¹⁷, Z¹⁸, Z¹⁹, Z²³, Z²⁴, Z²⁵, Z²⁶, Z²⁷, Z²⁸, Z³² and Z³³)        may, in one or more pairs of two, together with the atoms to        which they are bonded, form a carbocyclic, substituted        carbocyclic, heterocyclic or substituted heterocyclic group;-   p and r are independently selected from integers from 0 to 10    wherein, when q is 0, r is also 0; and-   q is an integer selected from 0 or 1.

By use of a respective effective amount of at least one compounddescribed herein, provided are methods of treating (includingameliorating) or preventing arrhythmias, atrial fibrillation, atrialflutter, supraventricular arrhythmias, gastrointestinal disorders (suchas reflux esauphagitis or a motility disorder), inflammatory orimmunological disease (such as chronic obstructive pulmonary disease),diabetes, cognitive disorders, migraine, epilepsy, hypertension, ortreating I_(Kur)-associated conditions, or controlling heart rate.

Also provided are pharmaceutical compositions comprising atherapeutically effective amount of at least one compound describedherein and a pharmaceutically acceptable vehicle or carrier thereof.Such compositions can further comprise at least one otheranti-arrhythmic agent (such as sotalol, dofetilide, diltiazem orVerapamil), or at least one calcium channel blocker, or at least oneanti-platelet agent (such as clopidogrel, cangrelor, ticlopidine,CS-747, ifetroban and aspirin), or at least one anti-hypertensive agent(such as a beta adrenergic blocker, ACE inhibitor (e.g., captopril,zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril,pentopril, quinapril, ramipril, or lisinopril), A H antagonist, ETantagonist, Dual ET/A II antagonist, or vasopepsidase inhibitor (e.g.,omapatrilat or gemopatrilat)), or at least one anti thrombotic/antithrombolytic agent (such as tPA, recombinant tPA, TNK, nPA, factor VIIainhibitors, factor Xa inhibitors (such as razaxaban), factor XIainhibitors or thrombin inhibitors), or at least one anti coagulant (suchas warfarin or a heparin), or at least one HMG-CoA reductase inhibitor(pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 or ZD-4522),or at least one anti diabetic agent (such as a biguanide or abiguanide/glyburide combination), or at least one thyroid mimetic, or atleast one mineralocorticoid receptor antagonist (such as spironolactoneor eplerinone), or at least one cardiac glycoside (such as digitalis orouabain).

Also provided is a method of synthesizing a compound of the invention,comprising forming a compound of formula I comprising a ring G from acompound of formula II:

wherein J is oxo or —O-Z*, where Z* is a leaving group. The ring-formingreactions can be, for example, one of those set forth in Schemes 1-17below (wherein —O-Z* is substituted for —OTs in Scheme 17).

DETAILED DESCRIPTION OF THE INVENTION

The terms “alk” or “alkyl” refer to straight or branched chainhydrocarbon groups having 1 to 12 carbon atoms, or 1 to 8 carbon atoms,such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl,pentyl, hexyl, heptyl, octyl, or any subset of the foregoing. Loweralkyl groups, that is, alkyl groups of 1 to 6 carbon atoms, aregenerally most preferred. The term “substituted alkyl” refers to alkylgroups substituted with one or more groups (such as by groups describedabove in the definition of R¹), such as selected from aryl, substitutedaryl, heterocyclo, substituted heterocyclo, carbocyclo, substitutedcarbocyclo, halo, hydroxy, alkoxy (optionally substituted), aryloxy(optionally substituted), alkylester (optionally substituted), arylester(optionally substituted), alkanoyl (optionally substituted), aryol(optionally substituted), cyano, nitro, amino, substituted amino, amido,lactam, urea, urethane and sulfonyl, or any subset of the foregoing.

The term “alkenyl” refers to straight or branched chain hydrocarbongroups having 2 to 12 carbon atoms, or 2 to 4 carbon atoms, and at leastone double carbon to carbon bond (either cis or trans), such as ethenyl.The term “substituted alkenyl” refers to alkenyl groups substituted withone or more groups (such as by groups described above in the definitionof R¹), such as selected from aryl, substituted aryl, heterocyclo,substituted heterocyclo, carbocyclo, substituted carbocyclo, halo,hydroxy, alkoxy (optionally substituted), aryloxy (optionallysubstituted), alkylester (optionally substituted), arylester (optionallysubstituted), alkanoyl (optionally substituted), aryol (optionallysubstituted), cyano, nitro, amino, substituted amino, amido, lactam,urea, urethane and sulfonyl, or any subset of the foregoing.

The term “alkynyl” refers to straight or branched chain hydrocarbongroups having 2 to 12 carbon atoms, or 2 to 4 carbon atoms, and at leastone triple carbon to carbon bond, such as ethynyl. The term “substitutedalkynyl” refers to alkynyl groups substituted with one or more groups(such as by groups described above in the definition of R¹), such asselected from aryl, substituted aryl, heterocyclo, substitutedheterocyclo, carbocyclo, substituted carbocyclo, halo, hydroxy, alkoxy(optionally substituted), aryloxy (optionally substituted), alkylester(optionally substituted), arylester (optionally substituted), alkanoyl(optionally substituted), aryol (optionally substituted), cyano, nitro,amino, substituted amino, amido, lactam, urea, urethane and sulfonyl, orany subset of the foregoing.

The term “alkylester” means alkyl-CO—O-alkyl or alkyl-O—CO-alkyl. Theterm “arylester” means aryl-CO—O-alkyl or aryl-O—CO-alkyl.

The terms “ar” or “aryl” refer to aromatic homocyclic (i.e.,hydrocarbon) mono-, bi- or tricyclic ring-containing groups such ashaving 6 to 12 members such as phenyl, naphthyl and biphenyl. Phenyl isa preferred aryl group. The term “substituted aryl” refers to arylgroups substituted with one or more groups (such as by groups describedabove in the definition of R¹), such as selected from alkyl, substitutedalkyl, alkenyl (optionally substituted), aryl (optionally substituted),heterocyclo (optionally substituted), halo, hydroxy, alkoxy (optionallysubstituted), aryloxy (optionally substituted), alkanoyl (optionallysubstituted), aroyl, (optionally substituted), alkylester (optionallysubstituted), arylester (optionally substituted), cyano, nitro, amino,substituted amino, amido, lactam, urea, urethane and sulfonyl, or anysubset of the foregoing, where optionally one or more pair ofsubstituents together with the atoms to which they are bonded form a 3to 7 member ring.

The terms “cycloalkyl” and “cycloalkenyl” refer to mono-, bi- or trihomocylcic ring groups of 3 to 15 carbon atoms which are, respectively,fully saturated and partially unsaturated. The term “cycloalkenyl”includes bi- and tricyclic ring systems that are not aromatic as awhole, but contain aromatic portions (e.g. fluorene,tetrahydronapthalene, dihydroindene, and the like). The rings ofmulti-ring cycloalkyl groups may be either fused, bridged and/or joinedthrough one or more spiro unions. The terms “substituted cycloalkyl” and“substituted cycloalkenyl” refer, respectively, to cycloalkyl andcycloalkenyl groups substituted with one or more groups (such as bygroups described above in the definition of R¹), such as selected fromaryl, substituted aryl, heterocyclo, substituted heterocyclo,carbocyclo, substituted carbocyclo, halo, hydroxy, alkoxy (optionallysubstituted), aryloxy (optionally substituted), alkylester (optionallysubstituted), arylester (optionally substituted), alkanoyl (optionallysubstituted), aryol (optionally substituted), cyano, nitro, amino,substituted amino, amido, lactam, urea, urethane and sulfonyl, or anysubset of the foregoing.

The terms “carbocyclo”, “carbocyclic” or “carbocyclic group” refer toboth cycloalkyl and cycloalkenyl groups. The terms “substitutedcarbocyclo”, “substituted carbocyclic” or “substituted carbocyclicgroup” refer to carbocyclo or carbocyclic groups substituted with one ormore groups as described in the definition of cycloalkyl andcycloalkenyl.

The terms “halogen” and “halo” refer to fluorine, chlorine, bromine andiodine.

The terms “heterocycle”, “heterocyclic”, “heterocyclic group” or“heterocyclo” refer to fully saturated or partially or completelyunsaturated, including aromatic (“heteroaryl”) or nonaromatic cyclicgroups (for example, 3 to 13 ring member monocyclic, 7 to 17 ring memberbicyclic, or 10 to 20 ring member tricyclic ring systems, such as, incertain embodiments, a monocyclic or bicyclic ring containing a total of3 to 10 ring atoms) which have at least one heteroatom in at least onecarbon atom-containing ring. Each ring of the heterocyclic groupcontaining a heteroatom may have 1, 2, 3 or 4 heteroatoms selected fromnitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen andsulfur heteroatoms may optionally be oxidized and the nitrogenheteroatoms may optionally be quaternized. The heterocyclic group may beattached at any heteroatom or carbon atom of the ring or ring system.The rings of multi-ring heterocycles may be either fused, bridged and/orjoined through one or more spiro unions.

Exemplary monocyclic heterocyclic groups include azetidinyl,pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl,imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl,isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl,isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl,piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrahydropyranyl,tetrazoyl, triazolyl, morpholinyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane andtetrahydro-1,1-dioxothienyl,

and the like.

Exemplary bicyclic heterocyclic groups include indolyl, benzothiazolyl,benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl,tetra-hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuiryl, benzofuranly, dihydrobenzofuranyl, chromonyl,coumarinyl, benzodioxolyl, dihydrobenzodioxolyl, benzodioxinyl,cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (suchas furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl),dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl, azabicycloalkyls(such as 6-azabicyclo[3.2.1]octane), azaspiroalkyls (such as 1,4dioxa-8-azaspiro[4.5]decane), imidazopyridinyl (such asimidazo[1,5-a]pyridin-3-yl), triazolopyridinyl (such as1,2,4-triazolo[4,3-a]pyridin-3-yl), and hexahydroimidazopyridinyl (suchas 1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyridin-3-yl),

and the like.

Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl,phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

The terms “substituted heterocycle”, “substituted heterocyclic”,“substituted heterocyclic group” and “substituted heterocyclo” refer toheterocycle, heterocyclic and heterocyclo groups substituted with one ormore groups (such as by groups described above in the definition of R¹),such as selected from alkyl, substituted alkyl, alkenyl, oxo, aryl,substituted aryl, heterocyclo, substituted heterocyclo, carbocyclo(optionally substituted), halo, hydroxy, alkoxy (optionallysubstituted), aryloxy (optionally substituted), alkanoyl (optionallysubstituted), aroyl (optionally substituted), alkylester (optionallysubstituted), arylester (optionally substituted), cyano, nitro, amido,amino, substituted amino, lactam, urea, urethane, sulfonyl, or anysubset of the foregoing, where optionally one or more pair ofsubstituents together with the atoms to which they are bonded form a 3to 7 member ring.

The term “alkanoyl” refers to alkyl group (which may be optionallysubstituted as described above) linked to a carbonyl group (i.e.—(O)-alkyl). Similarly, the term “aroyl” refers to an aryl group (whichmay be optionally substituted as described above) linked to a carbonylgroup (i.e., —C(O)-aryl).

Throughout the specification, groups and substituents thereof may bechosen to provide stable moieties and compounds.

The compounds of formula I form salts or solvates which are also withinthe scope of this invention. Reference to a compound of the formula Iherein is understood to include reference to salts thereof, unlessotherwise indicated. The term “salt(s)”, as employed herein, denotesacidic and/or basic salts formed with inorganic and/or organic acids andbases. In addition, when a compound of formula I contains both a basicmoiety and an acidic moiety, zwitterions (“inner salts”) may be formedand are included within the term “salt(s)” as used herein.Pharmaceutically acceptable (i.e., non-toxic, physiologicallyacceptable) salts are preferred, although other salts are also useful,e.g., in isolation or purification steps which may be employed duringpreparation. Salts of the compounds of the formula I may be formed, forexample, by reacting a compound I with an amount of acid or base, suchas an equivalent amount, in a medium such as one in which the saltprecipitates or in an aqueous medium followed by lyophilization.

The compounds of formula I which contain a basic moiety may form saltswith a variety of organic and inorganic acids. Exemplary acid additionsalts include acetates (such as those formed with acetic acid ortrihaloacetic acid, for example, trifluoroacetic acid), adipates,alginates, ascorbates, aspartates, benzoates, benzenesulfonates,bisulfates, borates, butyrates, citrates, camphorates,camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides(formed with hydrochloric acid), hydrobromides (formed with hydrogenbromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates(formed with maleic acid), methanesulfonates (formed withmethanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates,oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates,picrates, pivalates, propionates, salicylates, succinates, sulfates(such as those formed with sulfuric acid), sulfonates (such as thosementioned herein), tartrates, thiocyanates, toluenesulfonates such astosylates, undecanoates, and the like.

The compounds of formula I which contain an acidic moiety may form saltswith a variety of organic and inorganic bases. Exemplary basic saltsinclude ammonium salts, alkali metal salts such as sodium, lithium, andpotassium salts, alkaline earth metal salts such as calcium andmagnesium salts, salts with organic bases (for example, organic amines)such as benzathines, dicyclohexylamines, hydrabamines (formed withN,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines,N-methyl-D-glucamides, t-butyl amines, and salts with amino acids suchas arginine, lysine and the like.

Basic nitrogen-containing groups may be quaternized with agents such aslower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides,bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl,dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides), aralkyl halides(e.g. benzyl and phenethyl bromides), and others.

Prodrugs, and solvates thereof, of the compounds of the invention arealso contemplated herein. The term “prodrug”, as employed herein,denotes a compound which, upon administration to a subject, undergoeschemical conversion by metabolic or chemical processes to yield acompound of the formula I, or a salt and/or solvate thereof. Solvates ofthe compounds of formula I can be hydrates.

To the extent that compounds of the formula I, and salts thereof, mayexist in their tautomeric form, all such tautomeric forms arecontemplated herein as part of the present invention.

All stereoisomers of the present compounds, such as those which mayexist due to asymmetric carbons on the various substituents, includingenantiomeric forms (which may exist even in the absence of asymmetriccarbons) and diastereomeric forms, are contemplated within the scope ofthis invention. Individual stereoisomers of the compounds of theinvention may, for example, be substantially free of other isomers, ormay be admixed, for example, as racemates or with all other, or otherselected, stereoisomers. The chiral centers of the present invention canhave the S or R configuration as defined by the IUPAC 1974Recommendations.

The terms “including”, “such as”, “for example” and the like areintended to refer to exemplary embodiments and not to limit the scope ofthe present invention.

Exemplary Embodiments

It will be understood that any given exemplary embodiment can becombined with one or more additional exemplary embodiments.

In one embodiment of the invention, one or more of the groups accordingto the formula —(CH₂)_(p)-(Z¹)_(q)—(CH₂)_(r)-Z² is such that:

-   Z¹ is —CZ³Z⁴-, —O—, —NZ⁵-, —S—, —SO—, —SO₂—, —C(O)—, —C(O)Z⁶-,    —C(O)NZ⁷-, —C(S)—, —C(═NOZ⁸)-, alkyl, substituted alkyl, alkenyl,    substituted alkenyl, alkynyl, or substituted alkynyl; and/or-   Z² is hydrogen, —OZ⁹, —OC(O)Z¹⁰, —NZ⁵-C(O)-Z¹¹, —NZ¹²-CO₂-Z¹³,    —NZ¹⁴(C═O)—NZ¹⁵Z¹⁶, —NZ¹⁷Z¹⁸, —NO₂, halo, —CN, —C(O)Z¹⁹, —CO₂Z²⁰,    —C(S)Z²¹, —(C═NOZ²²)Z²³, —C(O)NZ²⁴Z²⁵, —C(S)NZ²⁶Z²⁷, —SZ²⁸, —SOZ²⁹,    —SO₂Z³⁰, —SO₂NZ³¹Z³², alkyl, substituted alkyl, alkenyl, substituted    alkenyl, alkynyl or substituted alkynyl, or, with respect to R⁷ may    further be aryl, substituted aryl, heteroaryl or substituted    heteroaryl; and/or-   Z⁵ is hydrogen, —C(O)Z²⁰, —CO₂Z²¹, —C(S)Z²², —(C═NOZ²³)Z²⁴,    —C(O)NZ²⁵Z²⁶, —C(S)NZ²⁷Z²⁸, —SZ²⁹, —SOZ³⁰, —SO₂Z³¹, —SO₂NZ³²Z³³,    alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,    substituted alkynyl, carbocyclo, substituted carbocyclo, aryl,    substituted aryl, heterocyclo (such as heteroaryl), or substituted    heterocyclo; and/or-   Z³, Z⁴, Z⁶, Z⁷, Z⁸, Z⁹, Z¹⁰, Z¹¹, Z¹², Z¹³, Z¹⁴, Z¹⁵, Z¹⁶, Z¹⁷, Z¹⁸,    Z¹⁹, Z²⁰, Z²¹, Z²², Z²³, Z²⁴, Z²⁵, Z²⁶, Z²⁷, Z²⁸, Z²⁹, Z³⁰, Z³¹, Z³²    and Z³³ are independently hydrogen, halo, alkyl, substituted alkyl,    alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl.

In certain embodiments, ring H is a six-membered ring. In someembodiments, n=2 and m=1.

In certain embodiments, ring G is according to one of the following: G AB D E 1 —N═ or —NR⁷— —N═ or —NR⁷— —CR⁶═ or —CR⁶— bond 2 —CR⁶═ or —CR⁶——N═ or —NR⁷— —N═ or —NR⁷— bond 3 —N═ or —NR⁷— —CR⁶═ or —CR⁶— —N═ or—NP⁷— bond 4 —O— —N═ or —NR⁷— —CR⁶═ or —CR⁶— bond 5 —N═ or —NR⁷— —O——CR⁶═ or —CR⁶— bond 6 —O— —NR⁷— —C(═O)— bond 7 —NR⁷— —O— —C(═O)— bond 8—CR⁶═ or —CR⁶— —N═ or —NR⁷— —O— bond 9 —CR⁶═ or —CR⁶— —O— —N═ or —NR⁷—bond 10 —N═ or —NR⁷— —N═ or —NR⁷— —S— bond 11 —N═ or —NR⁷— —CR⁶═ or—CR⁶— —S— bond 12 —N═ or —NR⁷— —CR⁶═ or —CR⁶— —N═ or —NR⁷— —CR⁶═ or—CR⁶— 13 —N═ or —NR⁷— —CR⁶═ or —CR⁶— —CR⁶═ or —CR⁶— CR⁶═ or —CR⁶—

In some embodiments of the invention, ring G is according to one of thefollowing formulas (oriented with ring atoms A, B, D and E (if present)situated in counterclockwise orientation as in formula I):

In certain embodiments, ring G is according to one of the above-listedrings further derivatized with one or more R⁷, the ring thereby losingone degree of unsaturation and gaining one hydrogen for each suchfurther derivatization of a ring nitrogen.

In certain embodiments, ring G is according to one of the above-listedrings with R⁶ in rings G-C through G-H and R⁶* in ring G-O equal tohydrogen.

In certain embodiments, R⁶* in ring G-O is OH or the tautomer.

In certain embodiments, ring G is according to ring G-K. In certainembodiments, ring G is according to ring G-K wherein R⁶ is hydrogen.

In some embodiments, ring G is a five-membered ring. In someembodiments, ring G is a six-membered ring. In some embodiments, ring Gis according to formula G-H. In certain embodiments, ring G is accordingto:

In some embodiments, Y comprises carbonyl or thiocarbonyl or a singlebond. In some embodiments, Y comprises carbonyl or a single bond. Insome embodiments, Y comprises carbonyl. In some embodiments, Y comprisesa single bond.

In some embodiments, R² is aryl or heteroaryl, which rings may besubstituted.

The substituents on R¹ and R² are one or more groups of the formula—(CH₂)_(p)-(Z¹)_(q)-(CH₂)_(r)-Z² or according to the description ofsubstitutions on the appropriate groups set forth above (e.g., aryl,heteroaryl, cycloalkyl, heterocyclo). In some embodiments suchsubstituents of R¹ or R² may, in one or more pairs of two, together withthe atoms to which they are bonded, form a carbocyclic, substitutedcarbocyclic, heterocyclic or substituted heterocyclic group.

In some embodiments, R³, R⁴, R⁵, R⁶ and R⁷ are independently accordingto the description of substitutions on the appropriate groups set forthabove, and such substituents may, in one or more pairs of two from amongR³, R⁴ and R⁵ or R⁶ and R⁷, together with the atoms to which they arebonded, form a carbocyclic, substituted carbocyclic, heterocyclic orsubstituted heterocyclic group.

In some embodiments, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are independentlyhydrogen, alkyl, substituted alkyl, alkenyl (optionally substituted),alkoxy (optionally substituted), alkanoyl (optionally substituted), oralkylester (optionally substituted).

In some embodiments, Z⁵ is hydrogen, —C(O)Z¹² or alkyl. In someembodiments, Z⁵ is hydrogen, alkanoyl or alkyl.

Scheme 1

Compounds of the formula I, where A is NR⁷ or N, B is N or NR⁷, D is CH,and E is a single or double bond may be prepared using Scheme 1:

{For simplicity, ring H in this and the following schemes is shown withn=2 and m=1, and without the optional substituents R³, R⁴ and R⁵.However, these variations can be used in the schemes.}

Compound 1 used in this preparation is readily prepared fromcommercially available reagents by methods well known to those skilledin the art and is directly commercially available when R¹ is phenyl.Protection of the ketone followed by reduction of the nitrile generatesamine 3. Acylation, alkylation or other derivatization with R²_Y_Z*(where Z* is a leaving group such as chloro) followed by ketalhydrolysis give ketone 4. Heating 4 with N,N-dimethylformamide dimethylacetal gives 5, which is cyclized to pyrazoles 6 and 7 upon heating withhydrazines in an alcoholic solvent.

In this and other schemes, embodiments in which N is substituted with R⁸can be made by by applying additional alkylation or acylation reactionsin an appropriate order (as will be recognized by those of ordinaryskill) or by driving the alkylation or acylation reactions to provide atwice derivatized amine.

Scheme 2

Compounds of the formula I, where A is O or N, B is N or O, D is CH andE is a bonds, may be prepared using Scheme 2:

Reacting 1 with hydroxylamine in tert-butanol gives predominatelyisoxazole 2. Reaction of 1 with hydroxylamine in pyridine givespredominately isoxazole 3.

Scheme 3

Compounds of the formula I, where A is NR⁷ or N, B is N or NR⁷, D is CHand E is a single or double bond, may be prepared using Scheme 3:

Formylation of 1 using potassium tert-butoxide and ethyl formategenerates the β-dicarbonyl species 2. Heating 2 with hydrazines in analcoholic solvent gives mixtures of pyrazoles 3 and 4.

Scheme 4

Compounds of the formula I, where A is NR⁷ or N, B is N or NR⁷, D is CHand E is a single or double bond, may be prepared using Scheme 4:

Condensation of 1 with a mixture of hydrazine and R⁷-Z* (such asR⁷*-SO₂-Z*) generates pyrazoles 2 and 3.

Scheme 5

Compounds of the formula I, where A is NR⁷ or N, B is CH, D is N or NR⁷and E is a bond, may be prepared using Scheme 5:

Bromination of ketone 1 gives 2. Heating 2 with formamide generatesimidazole 3. An addition reaction (such as sulfonylation) gives amixture of substituted imidazoles 4 and 5.

Scheme 6

Compounds of the formula I, where A is N, B is CR⁶, D is S and E is abond, may be prepared using Scheme 6:

Bromination of ketone 1 in acetic acid followed by cyclization using athioamide generates thiazole 2.

Scheme 7

Compounds of the formula I, where A is NR⁷ or N, B is N or NR⁷, D is CR⁶and E is a single or double bond, may be prepared using Scheme 7:

Deprotonation of 1 with LDA followed by C-acylation (see Tang et al.,Tetrahedron. Lett. 39, 2249-2252, 1998) generates the β-dicarbonylspecies 2. Heating 2 with hydrazines in an alcoholic solvent givespyrazoles 3 and 4. Note that where R⁶ in 2 is a leaving group, 3 and 4will have —OH in place of R⁶, which group may be tautomeric with acarbonyl form.

Scheme 8

Compounds of the formula I, where A is O or NR⁷, B is NR⁷ or O, D is C—Oand E is a bond, may be prepared using Scheme 8:

Reacting 1 with hydroxylamines in various solvents gives isoxazoles 2and/or 3.

Scheme 9

Compounds of the formula I, where A is N, B is N, D is S and E is abond, may be prepared using Scheme 9:

Condensation of 1 with tosylhydrazide give the hydrazone 2. Hurd-Moricyclization (see Stanetty et al., J. Heterocyclic Chem. 33, 1759, 1996)generates the thiadiazole 3.

Scheme 10

Compounds of the formula I, where A is CH, B is N or NR⁷, D is NR⁷ or N,and E is a single or double bond, may be prepared using Scheme 10:

Compound 1 used in this preparation is readily prepared fromcommercially available reagents by methods well known to those skilledin the art and is directly commercially available when R is ethyl.Nucleophilic attack at the ketone of 1 followed by hydrolysis leads toenone 2 (see Takeda et al., Chem. Pharm. Bull. 24: 1514-26, 1976).Conjugate addition using cyanide followed by protection of the ketonegives ketal 3. Reduction of the nitrile followed by acylation anddeprotection gives ketone 4. Condensation to give the β-carbonyl ketone5 followed by cyclization using hydrazine(s) generates pyrazoles 6 and7.

Scheme 11

Compounds of the formula I, where A is CH, B is N or O, D is O or N andE is a bond, may be prepared using Scheme 11:

Reacting 1 with hydroxylamine in tert-butanol gives predominatelyisoxazole 2. Reaction of 1 with hydroxylamine in pyridine givespredominately isoxazole 3.

Scheme 12

Compounds of the formula I, where A is NH, B is CR⁶, D is CR^(6*), whereCR⁶ and CR^(6*) form a phenyl, which may be substituted, and E is abond, may be prepared using Scheme 12:

Reaction of 1 with arylhydrazines gives indole 2.

Scheme 13

Compounds of the formula I, where A is N, B is CR⁶, D is N and E is CHmay be prepared using Scheme 13:

Compound 1 cyclizes to pyrimidine 2 upon heating with amidines in analcoholic solvent.

Scheme 14

Compounds of the formula I, where A is N, B is CR⁶, D is N and E is CHmay be prepared, for example in an enantiomerically enriched fashion,using Scheme 14:

Heating 1 with N,N-dimethylformamide dimethyl acetal followed bytransamination with an enantiomerically pure/enriched primary aminegives separable diastereomers of 2. Reaction of diastereomer 2 withamidines in an alcoholic solvent generated enantiomericallypure/enriched pyrimidine 3.

Scheme 15

Compounds of the formula I, where A is N, B is CR⁶, D is N and E isCR^(6*) (R^(6*) defined independently as is R⁶) may be prepared usingScheme 15:

Deprotonation of 1 with LDA followed by C-acylation (see Tang et al.,Tetrahedron. Lett. 39, 2249-2252, 1998) generates the β-dicarbonylspecies 2. Heating 2 with amidines in an alcoholic solvent givespyrimidine 3.

Scheme 16

Compounds of the formula I, where A is N, B is CR⁶, D is CR^(6*) and Eis CR^(6**) (R^(6**) defined independently as is R⁶) may be preparedusing Scheme 16:

Condensation of 1 with an O-allylhydroxylamine gives the oxime 2.Thermal rearrangement of 2 (see Koyama et al., Chem. Pharm. Bull. 31,2601-2606, 1983) generates pyridine 3.

Scheme 17

Compounds of the formula I, where A is C(OR^(6θ)), B is N and D is O maybe prepared using scheme 17. OR^(6θ)is selected from —O—(CH₂)_(r)—Z².

Reduction of 1 using RedAl gives the amino alcohol 2 which isselectively functionalized by acylation, alkylation or otherderivatization with R²-Y-Z* to give 3. Tosylation followed byelimination gives the olefin 5. Cycloaddition onto 5 gives isoxazolines6 and 7 which can be further functionalized by displacement reaction togive 8 and 9.

The 4-cyano-4-aryl cyclohexanone precursors are either commerciallyavailable or can be prepared according to published procedures (see,e.g., Swenton et al. J. Am. Chem. Soc. 97: 4941, 1975).

In instances where Y is a bond (Scheme 1, conversion of 3 to 4), oftentimes this reaction (where Z* is for example an activating group such astriflate or halogen) is catalyzed by a transition metal (usuallypalladium) to give N-(hetero)arylated products (see, e.g., Buchwald etal. J. Org. Chem. 65: 1144, 2000).

Methods describing the synthesis of fused heterocycles onto carbocyclicrings can be found for example in “Comprehensive Heterocyclic ChemistryII” Vol. 2-7, Katritzky, Rees and Scriven; 1996, Pergamon. Furtherexamples of similar but not limiting approaches toward the synthesis ofheterocycles fused to carbocyclic rings include: (a) Fromβ-carbonylcycloalkanones (see, e.g., Peterlin-Masic et al. Bioorg. Med.Chem. Lett. 13, 789, 2003. Fahrenholtz et al. J. Med. Chem. 15, 1056,1972); (b) From α-halocycloalkanones (see, e.g., Butler et al. J. Med.Chem. 30, 498, 1987; Wong et al. Synthesis 139, 1995); From cycloalkenesvia 1,3-dipolar cycloaddition (see, e.g., Witney et al. TetrahedronLett. 22, 3371, 1981; More general examples (see, e.g., “1,3-DipolarCycloaddition Chemistry” 2 Vols. Padwa, A.; 1984, Wiley).

R⁶, a substituent off carbon on the heterocyclic ring, can come from thereagent used for cyclization (as in Schemes 6, 13, 16) or can beincorporated prior to cyclization (as in Scheme 7) or both (as in Scheme15). It can also be incorporated via displacement of an appropriateleaving group on the heterocycle (as in Scheme 17). Also, in many cases,one can functionalize the heterocycle at carbon via metal-halogenexchange of an appropriate halogen-substituted heterocycle or by directdeprotonation at a ring C—H followed by acylation, alkylation or otherderivatization with R⁶-Z* (see, e.g., “The Chemistry of HeterocyclicCompounds” 60 Vols. Weissberger and Taylor; 1950-, Wiley).

R⁷, a substituent off nitrogen on the heterocyclic ring, can come fromthe reagent used (as in Schemes 1, 3, 7, 8, and 10) or can formed byacylation, alkylation or other derivitization with R⁷-Z* by methodsrecognized by those of ordinary skill.

Utility

Compounds within the scope of the present invention inhibit the Kv1subfamily of voltage-gated K+ channels, and as such are useful in thetreatment and/or prevention of various disorders: cardiac arrhythmias,including supraventricular arrhythmias, atrial arrhythmias, atrialflutter, atrial fibrillation, complications of cardiac ischemia, and useas heart rate control agents; angina pectoris including relief ofPrinzmetal's symptoms, vasospastic symptoms and variant symptoms;gastrointestinal disorders including reflux esauphagitis, functionaldispepsia, motility disorders (including constipation and diarrhea), andirritable bowel syndrome; disorders of vascular and visceral smoothmuscle including asthma, chronic obstructive pulmonary disease, adultrespiratory distress syndrome, peripheral vascular disease (includingintermittent claudication), venous insufficiency, impotence, cerebraland coronary spasm and Raynaud's disease; inflammatory and immunologicaldisease including inflammatory bowel disease, rheumatoid arthritis,graft rejection, asthma. chronic obstructive pulmonary disease, cysticfibrosis and atherosclerosis; cell poliferative disorders includingrestenosis and cancer (including leukemia); disorders of the auditorysystem; disorders of the visual system including macular degenerationand cataracts; diabetes including diabetic retinopathy, diabeticnephropathy and diabetic neuropathy; muscle disease including myotoniaand wasting; peripheral neuropathy; cognitive disorders; migraine;memory loss including Alzheimer's and dementia; CNS mediated motordysfunction including Parkinson's disease, and ataxia; epilepsy; andother ion channel mediated disorders.

As inhibitors of the Kv1 subfamily of voltage-gated K+ channelscompounds of the present invention are useful to treat a variety offurther disorders including resistance by transplantation of organs ortissue, graft-versus-host diseases brought about by medulla ossiumtransplantation, rheumatoid arthritis, systemic lupus erythematosus,hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type Idiabetes uveitis, juvenile-onset or recent-onset diabetes mellitus,posterior uveitis, allergic encephalomyelitis, glomerulonephritis,infectious diseases caused by pathogenicmicroorganisms, inflammatory andhyperproliferative skin diseases, psoriasis, atopical dermatitis,contact dermatitis, eczematous dermatitises, seborrhoeis dermatitis,Lichen planus, Pemphigus, bullous pemphigoid, Epidermolysis bullosa,urticaria, angioedemas, vasculitides, erythemas, cutaneouseosinophilias, Lupus erythematosus, acne, Alopecia greata,keratoconjunctivitis, vernal conjunctivitis, uveitis associated withBehcet's disease, keratitis, herpetic keratitis, conical cornea,dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus,Mooren's ulcer Scleritis, Graves' opthalmopathy, Vogt-Koyanagi-Haradasyndrome, sarcoidosis, pollen allergies, reversible obstructive airwaydisease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsicasthma, dust asthma, chronic or inveterate asthma, late asthma andairway hyper-responsiveness, bronchitis, gastric ulcers, vascular damagecaused by ischemic diseases and thrombosis, ischemic bowel diseases,inflammatory bowel diseases, necrotizing enterocolitis, intestinallesions associated with thermal burns and leukotriene B4-mediateddiseases, Coeliaz diseases, proctitis, eosinophilic gastroenteritis,mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis,eczema, interstitial nephritis, Good-pasture's syndrome,hemolytic-uremic syndrome, diabetic nephropathy, multiple myositis,Guillain-Barre syndrome, Meniere's disease, polyneuritis, multipleneuritis, mononeuritis, radiculopathy, hyperthroidism, Basedow'sdisease, pure red cell aplasia, aplastic anemia, hypoplastic anemia,idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia,agranulocytosis, pernicious anemia, megaloblastic anemia,anerythroplasia, osteoporosis, sarcoidosis, fibroid lung, idopathicinterstitial pneumonia, dermatomyositis, leukoderma vulgaris, ichthyosisvulgaris, photoallergic sensitivity, cutaneous T cell lymphoma,arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritisnodosa, myocardosis, scleroderma, Wegener's granuloma, Sjogren'ssyndrome, adiposis, eosinophilic fascitis, lesions of gingiva,periodontium, alveolar bone, substantia osses dentis,glomerulonephritis, male pattern alopecia or alopecia senilis bypreventing epilation or providing hair germination and/or promoting hairgeneration and hair growth, muscular dystrophy; Pyoderma and Sezary'ssyndrome, Addison's disease, ischemia-reperfusion injury of organs whichoccurs upon preservation, transplantation or ischemic disease,endotoxin-shock, pseudomembranous colitis, colitis caused by drug orradiation, ischemic acute renal insufficiency, chronic renalinsufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer,pulmonary emphysema, cataracta, siderosis, retinitis, pigentosa, senilemacular degeneration, vitreal scarring, corneal alkali burn, dermatitiserythema multiforme, linear IgA ballous dermatitis and cementdermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseasescaused by environmental pollution, aging, carcinogenis, metastatis ofcarcinoma and hypobaropathy, disease caused by histamine orleukotriene-C4 release, Behcet's disease, autoimmune hepatitis, primarybiliary cirrhosis sclerosing cholangitis, partial liver resection, acuteliver necrosis, necrosis caused by toxin, viral hepatitis, shock, oranoxia, B-virus hepatitis, non-A/non-B hepatitis, cirrhosis, alcoholiccirrhosis, hepatic failure, fulminant hepatic failure, late-onsethepatic failure, “acute-on-chronic” liver failure, augention ofchemotherapeutic effect, cytomegalovirus infection, HCMV infection,AIDS, cancer, senile dementia, trauma, and chronic bacterial infection.

The compounds of the present invention are antiarrhythmic agents whichare useful in the prevention and treatment (including partialalleviation or cure) of arrhythmias. As inhibitors of Kv1.5, compoundswithin the scope of the present invention are particularly useful in theselective prevention and treatment of supraventricular arrhythmias suchas atrial fibrillation, and atrial flutter. By “selective prevention andtreatment of supraventricular arrhythmias” is meant the prevention ortreatment of supraventricular arrhythmias wherein the ratio of theprolongation of the atrial effective refractory period to theprolongation of the ventricular effective refractory period is greaterthan 1:1. This ratio is preferably greater than 4:1, more preferablygreater than 10:1, and most preferably such that prolongation of theatrial effective refractory response period is achieved withoutsignificantly detectable prolongation of the ventricular effectiverefractory period.

In addition, the compounds within the scope of the present inventionblock IKur, and thus may be useful in the prevention and treatment ofall IKur-associated conditions. An “IKur-associated condition” is adisorder which may be prevented, partially alleviated or cured by theadministration of an IKur blocker. The Kv1.5 gene is known to beexpressed in stomach tissue, intestinal/colon tissue, the pulmonaryartery, and pancreatic beta cells. Thus, administration of an IKurblocker can provide useful treatment for disorders such as: refluxesauphagitis, functional dispepsia, constipation, asthma, and diabetes.Additionally, Kv1.5 is known to be expressed in the anterior pituitary.Thus, administration of an IKur blocker can stimulate growth hormonesecretion. IKur inhibitors can additionally be useful in cellpoliferative disorders such as leukemia, and autoimmune diseases such asrheumatoid arthritis and transplant rejection.

The present invention thus provides methods for the prevention ortreatment of one or more of the aforementioned disorders, comprising thestep of administering to a subject in need thereof an effective amountof at least one compound of the formula I. Other therapeutic agents suchas those described below may be employed with the inventive compounds inthe present methods. In the methods of the present invention, such othertherapeutic agent(s) may be administered prior to, simultaneously withor following the administration of the compound(s) of the presentinvention.

The present invention also provides pharmaceutical compositionscomprising at least one of the compounds of the formula I or saltsthereof capable of preventing or treating one or more of theaforementioned disorders in an amount effective therefor, and apharmaceutically acceptable vehicle or diluent. The compositions of thepresent invention may contain other therapeutic agents as describedbelow, and may be formulated, for example, by employing conventionalsolid or liquid vehicles or diluents, as well as pharmaceuticaladditives of a type appropriate to the mode of desired administration(for example, excipients, binders, preservatives, stabilizers, flavors,etc.) according to techniques such as those well known in the art ofpharmaceutical formulation.

The compounds of the formula I may be administered by any suitablemeans, for example, orally, such as in the form of tablets, capsules,granules or powders; sublingually; bucally; parenterally, such as bysubcutaneous, intravenous, intramuscular, or intrastemal injection orinfusion techniques (e.g., as sterile injectable aqueous or non aqueoussolutions or suspensions); nasally such as by inhalation spray;topically, such as in the form of a cream or ointment; or rectally suchas in the form of suppositories; in dosage unit formulations containingnon toxic, pharmaceutically acceptable vehicles or diluents. The presentcompounds may, for example, be administered in a form suitable forimmediate release or extended release. Immediate release or extendedrelease may be achieved by the use of suitable pharmaceuticalcompositions comprising the present compounds, or, particularly in thecase of extended release, by the use of devices such as subcutaneousimplants or osmotic pumps. In the case where the compounds of formula Iare being administered to prevent or treat arrhythmias, the compoundsmay be administered to achieve chemical conversion to normal sinusrhythm, or may optionally be used in conjunction with electricalcardioconversion.

Exemplary compositions for oral administration include suspensions whichmay contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which may contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The compounds of formula I may also be delivered through theoral cavity by sublingual and/or buccal administration. Molded tablets,compressed tablets or freeze-dried tablets are exemplary forms which maybe used. Exemplary compositions include those formulating the presentcompound(s) with fast dissolving diluents such as mannitol, lactose,sucrose and/or cyclodextrins. Also included in such formulations may behigh molecular weight excipients such as celluloses (avicel) orpolyethylene glycols (PEG). Such formulations may also include anexcipient to aid mucosal adhesion such as hydroxy propyl cellulose(HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methylcellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agentsto control release such as polyacrylic copolymer (e.g., Carbopol 934).Lubricants, glidants, flavors, coloring agents and stabilizers may alsobe added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions in saline which may contain, for example, benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, and/or other solubilizing or dispersing agents such asthose known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which may contain, for example, suitable nontoxic, parenterally acceptable diluents or solvents, such as mannitol,1,3 butanediol, water, Ringer's solution, an isotonic sodium chloridesolution, or other suitable dispersing or wetting and suspending agents,including synthetic mono- or diglycerides, and fatty acids, includingoleic acid.

Exemplary compositions for rectal administration include suppositorieswhich may contain, for example, a suitable non irritating excipient,such as cocoa butter, synthetic glyceride esters or polyethyleneglycols, which are solid at ordinary temperatures, but liquify and/ordissolve in the rectal cavity to release the drug.

Exemplary compositions for topical administration include a topicalcarrier such as Plastibase (mineral oil gelled with polyethylene).

The effective amount of a compound of the present invention may bedetermined by one of ordinary skill in the art, and includes exemplarydosage amounts for an adult human of from about 0.001 to 100 mg/kg ofbody weight of active compound per day, which may be administered in asingle dose or in the form of individual divided doses, such as from 1to 4 times per day. It will be understood that the specific dose leveland frequency of dosage for any particular subject may be varied andwill depend upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the species, age, body weight, general health, sex anddiet of the subject, the mode and time of administration, rate ofexcretion, drug combination, and severity of the particular condition.Preferred subjects for treatment include animals, most preferablymammalian species such as humans, and domestic animals such as dogs,cats and the like, subject to the aforementioned disorders.

The compounds of the present invention may be employed alone or incombination with each other and/or other suitable therapeutic agentsuseful in the treatment of the aforementioned disorders or otherdisorders, including: other antiarrhythmic agents such as Class I agents(e.g., propafenone), Class II agents (e.g., carvadiol and propranolol),Class III agents (e.g., sotalol, dofetilide, amiodarone, azimilide andibutilide), Class IV agents (e.g., diltiazem and verapamil), 5HTantagonists (e.g., sulamserod, serraline and tropsetron), anddronedarone; calcium channel blockers (both L-type and T-type) such asdiltiazem, verapamil, nifedipine, amlodipine and mybefradil;Cyclooxygenase inibitors (i.e., COX-1 and/or COX-2 inhibitors) such asaspirin, indomethacin, ibuprofen, piroxicam, naproxen, celebrex, vioxxand NSAIDs; anti-platelet agents such as GPIIb/IIIa blockers (e.g.,abciximab, eptifibatide and tirofiban), P2Y12 antagonists (e.g.,clopidogrel, cangrelor, ticlopidine and CS-747), P2Y1 antagonists,thromboxane receptor antagonists (e.g., ifetroban), aspirin, and PDE-IIIinhibitors (e.g., dipyridamole) with or without aspirin; diruetics suchas chlorothiazide, hydrochlorothiazide, flumethiazide,hydroflumethiazide, bendroflumethiazide, methylchlorothiazide,trichloromethiazide, polythiazide, benzthiazide, ethacrynic acidtricrynafen, chlorthalidone, furosemide, musolimine, bumetanide,triamtrenene, armiloride, and spironolactone; anti-hypertensive agentssuch as alpha adrenergic blockers, beta adrenergic blockers, calciumchannel blockers, diuretics, renin inhibitors, ACE inhibitors, (e.g.,captropril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril,delapril, pentopril, quinapril, ramipril, lisinopril), A II antagonists(e.g., losartan, irbesartan, valsartan), ET antagonists (e.g.sitaxsentan, atrsentan and compounds disclosed in U.S. Pat. Nos.5,612,359 and 6,043,265), Dual ET/AII antagonist (e.g., compoundsdisclosed in WO 00/01389), neutral endopeptidase (NEP) inhibitors,vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilatand gemopatrilat), nitrates, and combinations of such anti-hypertensiveagents; antithrombotic/thrombolytic agents such as tissue plasminogenactivator (tPA), recombinant tPA, tenecteplase (TNK), lanoteplase (nPA),factor VIIa inhibitors, factor Xa inhibitors (such as razaxaban), XIainhibitors, thromin inibitors (e.g., hirudin and argatroban), PAI-1inhibitors (i.e., inactivators of tissue plasminogen activatorinhibitors), α2-antiplasmin inhibitors, streptokinase, urokinase,prourokinase, anisoylated plasminogen streptokinase activator complex,and animal or salivary gland plasminogen activators; anticoagulants suchas warfarin and heparins (including unfractionated and low molecularweight heparins such as enoxaparin and dalteparin); HMG-CoA reductaseinhibitors such as pravastatin lovastatin, atorvastatin, simvastatin,NK-104 (a.k.a. itavastatin, or nisvastatin or nisbastatin) and ZD-4522(a.k.a. rosuvastatin, or atavastatin or visastatin); othercholesterol/lipid lowering agents such as squalene synthetaseinhibitors, fibrates, and bile acid sequestrants (e.g., questran);antipoliferative agents such as cyclosporin A, taxol, FK 506, andadriamycin; antitumor agents such as taxol, adriamycin, epothilones,cisplatin and carboplatin; anti-diabetic agents such as biguanides (e.g.metformin), glucosidase inhibitors (e.g. acarbose), insulins,meglitinides (e.g. repaglinide), sulfonylureas (e.g. glimepiride,glyburide and glipizide), biguanide/glyburide combinations (i.e,glucovance), thiozolidinediones (e.g. troglitazone, rosiglitazone andpioglitazone), PPAR-gamma agonists, aP2 inhibitors, and DP4 inhibitors;thyroid mimetics (including thyroid receptor antagonists) (e.g.,thyrotropin, polythyroid, KB-130015, and dronedarone); Mineralocorticoidreceptor antagonists such as spironolactone and eplerinone; growthhormone secretagogues; anti-osteoporosis agents (e.g., alendronate andraloxifene); hormone replacement therapy agents such as estrogen(including conjugated estrogens in premarin), and estradiol;antidepressants such as nefazodone and sertraline; antianxiety agentssuch as diazepam, lorazepam, buspirone, and hydroxyzine pamoate; oralcontraceptives; anti-ulcer and gastroesophageal reflux disease agentssuch as famotidine, ranitidine, and omeprazole; anti-obesity agents suchas orlistat; cardiac glycosides including digitalis and ouabain;phosphodiesterase inibitors including PDE III inhibitors (e.g.cilostazol), and PDE V inhibitors (e.g., sildenafil); protein tyrosinekinase inhibitors; steroidal anti-inflammatory agents such asprednisone, and dexamethasone; and other anti-inflammatory agents suchas enbrel. The combinations can be co-formulated or in the form of kitspackaged to provide appropriate dosages for co-administration.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art.

Assays to determine the degree of activity of a compound as an IKurinhibitor are well known in the art and are described in references suchas J. Gen. Physiol. Apr; 101(4):513-43, and Br. J. Pharmacol. 1995 May;115(2):267-74.

Assays to determine the degree of activity of a compound as an inhibitorof other members of the Kv1 subfamily are also well known in the art.For example, inhibition of Kv1.1, Kv1.2 and Kv1.3 can be measured usingprocedures described by

Grissmer S, et al., Mol Pharmacol 1994 June; 45(6):1227-34. Inhibitionof Kv1.4 can be measured using procedures described by Petersen K R, andNerbonne J M, Pflugers Arch 1999 February; 437(3):381-92. Inhibition ofKv1.6 can be measured using procedures described by Bowlby M R, andLevitan I B, J Neurophysiol 1995 June; 73(6):2221-9. And inhibition ofKv1.7 can be measured using procedures described by Kalman K, et al., JBiol Chem 1998 Mar. 6;273(10):5851-7.

The following examples further illustrate the present invention, but ofcourse, should not be construed as in any way limiting its scope.

EXAMPLES Example 1 Racemic2-Methoxy-N-(5-phenyl-4,5,6,7-tetrahydro-2H-indazol-5-ylmethyl)-benzamide

Compound 1: Compound 1 is commercially available from Aldrich(Milwaukee, Wis.).

Compound 2: To a solution of 4-phenyl-4-cyano-cyclohexane-1-one 1 (10 g,50 mmol) in toluene (200 mL) was added p-toluenesulfonic acidmonohydrate (2.5 g, 13.1 mmol) followed by ethylene glycol (20 ml, 360mmol). A Dean-Stark trap was attached and the reaction heated at refluxfor 5 hours. Volatiles were removed in vacuo and the residue brought upinto EtOAc (200 ml) and washed with aq. NaHCO₃ (2×50 ml) and brine (50ml). The organic layer was dried over (MgSO₄), filtered, andconcentrated in vacuo to provide 2 as an oil (12.2 g, >95%), which wasused in the following reaction without further purification.

Compound 3: To a solution of 2 (12.9 g, 50 mmol) in THF (100 mL) wasadded dropwise via cannula a 1.0 M solution of LAH in THF (60 ml, 60mmol) The resulting solution was stirred at reflux for 2 hours thencooled to 0° C. and carefully quenched with 4N NaOH (4 mL). The mixturewas filtered through a short pad of Na₂SO₄ and the filter cake washedwith THF. Volatiles were removed in vacuo to provide 3 an oil (11.3g, >90%), which was subjected to the following reaction without furtherpurification.

Compound 4: To a solution of 3 (5.7 g, 23 mmol) in dichloromethane (100mL) at 0° C. was added triethylamine (5.7 mL, 41 mmol) followed bydropwise addition of anisoyl chloride (4.3 ml, 29 mmol) and theresulting solution was stirred for 2.5 hours. Volatiles were removed invacuo and the residue brought up into EtOAc (200 ml) and washed with aq.NaHCO₃ (50 ml). The organic layer was dried (MgSO₄), filtered andconcentrated in vacuo. The residue was brought up into THF (50 mL) then2N aq. HCl (50 mL) added and the resulting solution was stirred for 16hours. The reaction mixture was diluted with EtOAc (200 ml) and washedwith brine (2×50 ml), dried (MgSO₄), filtered, and volatiles removed toleave a white solid. Crystallization of this material from EtOAc/hexanesgave 4 (6.5 g, 84% yield) as a white solid. ¹H NMR (CDCl₃, 500 mHz) δ2.13 (m, 2H), 2.32 (m, 2H), 2.50 (m, 4H), 3.64 (s, 3H), 3.77 (s, 1H),3.78 (s, 1H), 6.88 (d, 1H, J=8.3 Hz), 7.06 (dt, 1H, J=1.7 and 5.5 Hz),7.42 (dt, 1H, J=1.6 and 7.2 Hz) 7.49 (m, 4H), 7.68 (bt, 1H), 8.20 (dd,1H, J=1.7 and 8.2 Hz).

Compound 5: To a suspension of 4 (500 mg, 1.48 mmol) in DMF (0.2 mL) wasadded N,N-dimethylformamide dimethylacetal (0.22 mL, 1.55 mmol) and theresulting mixture was heated in a 110° C. oil bath for 20 hours. Aftercooling to room temperature, volatiles were removed under a stream ofnitrogen then the residue placed under vacuum to leave 5 (610 mg, >90%yield) as a brown viscous oil containing trace amounts of solvent thatwas used without purification. [M+H]=393.

Compound 6: To a solution of 5 (55 mg, 0.14 mmol) in MeOH (0.7 mL) wasadded hydrazine monohydrate (0.007 mL, 0.14 mmol) and the reactionstirred for 18 hours. Volatiles were removed under a stream of nitrogenthen the residue chromatographed with May 25, 1970 MeOH/hexanes/EtOAc togive 6 (23 mg, 45% yield) as a clear oil. Rt=1.42 min using Phenomenex30×4.6 5u C18 column (Torrance, CA) with flow rate of 5 mL/min over 2min gradient. 0 to 100% B. Solvent A=10/90/0.1% MeOH/H₂O/TFA. SolventB=90/10/0.1%. [M+H]=362.

Example 2

Example 2 was synthesized using methodology described in example 1. ExStructure Name M + H 2

2-Methoxy-N-(2-methyl-5-phenyl-4,5,6,7-tetrahydro-2H-indazol-5-ylmethyl)-benzamide 376

Example 3 2-Methoxy-N-(5-phenyl-4,5,6,7-tetrahydro-benzo[d]isoxazol-5-ylmethyl)-benzamide

Compound 1: Compound 1 was synthesized as described in example 1.

Compound 2: To a solution of 1 (20 mg, 0.051 mmol) in hot tert-butanol(1 mL) was added hydroxylamine hydrochloride (4.1 mg, 0.06 mmol) and thereaction heated at reflux for 1.5 hours. The solution was cooled to roomtemperature then the solvent removed under a stream of nitrogen. Theresidue was purified by prep HPLC (Rt=15.2 min using a Shimadzu S5VP-ODS 20×100 mm column (Kyoto, JP) with flow rate of 20 mL/min over 30min gradient. 0 to 100% B. Solvent A=10/90/0.1% MeOH/H2O/TFA. SolventB=90/10/0.1%) to give 2 (5.1 mg, 28% yield) as a clear oil. M+H=363.

Example 4 2-Methoxy-N-(5-phenyl-4,5,6,7-tetrahydro-benzo[c]isoxazol-5-ylmethyl)-benzamide

Compound 1: Compound 1 was synthesized as described in example 1.

Compound 2: To a solution of 1 (20 mg, 0.051 mmol) in pyridine (0.5 mL)was added a solution of hydroxylamine hydrochloride (8.9 mg, 0.13 mmol)in H₂O (0.050 mL) and the reaction heated at reflux for 5 hours. Thesolution was cooled to room temperature then the solvent removed under astream of nitrogen. The residue was chromatographed on silica gel elutedwith 50/50 EtOAc/hexanes to give 2 (8 mg, 45% yield) as a clear oil.Rt=1.61 min using Phenomenex 30×4.6 5u column with flow rate of 5 mL/minover 2 min gradient. 0 to 100% B. Solvent A=10/90/0.1% MeOH/H₂O/TFA.Solvent B=90/10/0.1%. M+H=363.

Examples 5 and 6N-(1,5-Diphenyl-4,5,6,7-tetrahydro-1H-indazol-5-ylmethyl)-2-methoxy-benzamide;andN-(2,5-Diphenyl-4,5,6,7-tetrahydro-2H-indazol-5-ylmethyl)-2-methoxy-benzamide

Compound 1: The synthesis of compound 1 is described in example 1.

Compound 2: To a flask charged with 1 (515 mg, 1.53 mmol) was added a1.0 M solution of potassium tert-butoxide in tert-butanol (5.50 mL, 5.50mmol) and the reaction stirred for 15 minutes turning homogeneous, thenethyl formate (0.44 mL, 5.50 mmol) was added dropwise (gas evolution)and the reaction stirred for 1 hour. The reaction was quenched by theaddition of satd NH₄Cl (15 mL) then extracted with CHCl₃ (15 ml). Theorganic layer was washed with brine (10 mL), dried (MgSO₄), filtered,and concentrated in vacuo to provide 2 as a white solid (620 mg, >95%),which was used in the following reaction without further purification.

Compounds 3 and 4: To a solution of 2 (30 mg, 0.08 mmol) in MeOH (0.4mL) was added phenylhydrazine (0.008 mL, 0.08 mmol) and the reactionstirred for 14 hours at room temperature then heated at 60° C. for 16hours. Volatiles were removed under a stream of nitrogen then theresidue was chromatographed by prep TLC eluting with 3/97 MeOH/CH₂Cl₂ (4elutions) to give the less polar isomer 3 (10 mg, 29% yield) and themore polar isomer 4 (10 mg, 29% yield) as white solids. Rt=1.897 and1.893 min for 3 and 4, respectively, using Phenomenex 30×4.6 5u columnwith flow rate of 5 mL/min over 2 min gradient. 0 to 100% B. SolventA=10/90/0.1% MeOH/H₂O/TFA. Solvent B=90/10/0.1%. [M+H]=438.

Examples 7 to 13

Examples 7 to 13 were synthesized using methodology described inexamples 5 and 6. Ex Structure Name M + H  7

N-[1-(2-Hydroxy-ethyl)-5-phenyl-4,5,6,7-tetrahydro-1H-indazol-5-ylmethyl]-2-methoxy- benzamide 406  8

N-[2-(2-Hydroxy-ethyl)-5-phenyl-4,5,6,7-tetrahydro-2H-indazol-5-ylmethyl]-2-methoxy- benzamide 406  9

N-[1-(6-Chloro-pyridazin-3-yl)-5-phenyl-4,5,6,7-tetrahydro-1H-indazol-5-ylmethyl]-2-methoxy- benzamide 475 10

N-[2-(6-Chloro-pyridazin-3-yl)-5-phenyl-4,5,6,7-tetrahydro-2H-indazol-5-ylmethyl]-2-methoxy- benzamide 475 11

N-(2-tert-Butyl-5-phenyl-4,5,6,7-tetrahydro-2H-indazol-5-ylmethyl)-2-methoxy-benzamide 419 12

N-(1-Benzyl-5-phenyl-4,5,6,7-tetrahydro-1H-indazol-5-ylmethyl)-2-methoxy-benzamide 453 13

N-(2-Benzyl-5-phenyl-4,5,6,7-tetrahydro-2H-indazol-5-ylmethyl)-2-methoxy-benzamide 453

Examples 14 and 152-Methoxy-N-[5-phenyl-2-(propane-2-sulfonyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylmethyl]-benzamide;and2-Methoxy-N-[5-phenyl-1-(propane-2-sulfonyl)-4,5,6,7-tetrahydro-1H-indazol-5-ylmethyl]-benzamide

Compound 1: The synthesis of compound 1 is described in examples 5 and6.

Compound 2: To a vial charged with hydrazine (5.4 mg, 0.17 mmol) inCH₂Cl₂ (0.25 mL) at 0° C. was added 2-propanesulfonylchloride (23 mg,0.16 mmol) over a 15 minute period then the suspension stirred for 1hour. A solution of 1 (40 mg, 0.11 mmol) in CH₂Cl₂ (0.20 mL) was addedfollowed by AcOH (0.23 mL) and the reaction allowed to warm to roomtemperature and stirred for 16 hours. H₂O (1 mL) was added and thereaction was extracted with CH₂Cl₂ (3×1 mL) then the combined organicswashed with satd NaHCO₃ (1 mL), dried (Na₂SO₄), filtered, andconcentrated in vacuo. The residue was purified by HPLC using aPhenomenex Luna 5u C18 30×250 mm preparative column (flow rate of 30mL/min over 20 min gradient. 55 to 80% B. Solvent A=10/90/0.1%MeOH/H₂O/TFA, Solvent B=90/10/0.1%) to give the more polar isomer 3 (4.4mg, 9% yield) and the less polar isomer 2 (7.0 mg, 14% yield) as whitesolids. Rt=1.73 and 1.70 min for 2 and 3, respectively, using Phenomenex30×4.6 mm 5u analytical column (flow rate of 5 mL/min over 2 mingradient. 0 to 100% B. Solvent A=10/90/0.1% MeOH/H₂O/TFA. SolventB=90/10/0.1%). [M+H]=468 for both 2 and 3.

Examples 16 to 24

Examples 16 to 24 were synthesized using methodology described inexamples 14 and 15. Ex Structure Name M + H 16

N-(2-Methanesulfonyl-5-phenyl-4,5,6,7-tetrahydro-2H-indazol-5-ylmethyl)-2-methoxy- benzamide 441 17

2-Methoxy-N-[1-(1-methyl-1H-imidazole-4-sulfonyl)-5-phenyl-4,5,6,7-tetrahydro-1H- indazol-5-ylmethyl]-benzamide507 18

2-Methoxy-N-[2-(1-methyl-1H-imidazole-4-sulfonyl)-5-phenyl-4,5,6,7-tetrahydro-2H- indazol-5-ylmethyl]-benzamide507 19

2-Methoxy-N-[5-phenyl-2-(2,3,4-trifluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-2H-indazol- 5-ylmethyl]-benzamide557 20

2-Methoxy-N-[5-phenyl-1-(2,3,4-trifluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-indazol- 5-ylmethyl]-benzamide557 21

N-[2-(5-Chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl)-5-phenyl-4,5,6,7-tetrahydro-2H-indazol-5-ylmethyl]-2-methoxy-benzamide 555 22

N-[1-(5-Chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl)-5-phenyl-4,5,6,7-tetrahydro-1H-indazol-5-ylmethyl]-2-methoxy-benzamide 555 23

N-[2-(3,5-Dimethyl-isoxazole-4-sulfonyl)-5-phenyl-4,5,6,7-tetrahydro-2H-indazol-5- ylmethyl]-2-methoxy-benzamide522 24

N-[1-(3,5-Dimethyl-isoxazole-4-sulfonyl)-5-phenyl-4,5,6,7-tetrahydro-1H-indazol-5- ylmethyl]-2-methoxy-benzamide522

Example 252-Methoxy-N-(5-phenyl-4,5,6,7-tetrahydro-1H-benzoimidazol-5-ylmethyl)-benzamide

Compound 1: The synthesis of compound 1 is described in example 1.

Compound 2: To a solution of 1 (450 mg, 1.33 mmol) in THF (10 mL) at 0°C. was added a cooled (0° C.) solution of phenyltrimethylammoniumtribromide (552 mg, 1.47 mmol) in THF (5 mL) rapidly via cannula and thereaction stirred for 15 minutes, turning from orange to a pale yellow.The reaction was poured into brine (50 mL) and extracted with Et₂O (2×50mL), dried (MgSO₄), filtered and concentrated in vacuo to leave 3 (550mg, >95% yield) as a white solid which was used in the followingreaction without further purification.

Compound 3: To a vial charged with 1 (295 mg, 0.71 mmol) was addedformamide (3 mL) then the reaction sealed and heated in a 180° C.oil-bath for 1.5 hours. The solution was cooled to room temperature, 0.5N HCl (6 mL) added, then extracted with CH₂Cl₂ (2×6 mL). To the aqueouslayer was added ammonium hydroxide until a pH of 9 was reached, thenextracted with EtOAc (2×6 mL). The organics were dried (MgSO₄), filteredand concentrated in vacuo to leave 3 (47 mg, 18% yield) as a pale yellowviscous oil. Rt=2.29 min using a Phenomenex 30×4.6 5u column with flowrate of 4 mL/min over 4 min gradient. 0 to 100% B. Solvent A=10/90/0.1%MeOH/H₂O/H3PO4. Solvent B=90/10/0.1%.

Examples 26 and 27N-[1-(3,5-Dimethyl-isoxazole-4-sulfonyl)-5-phenyl-4,5,6,7-tetrahydro-1H-benzoimidazol-5-ylmethyl]-2-methoxy-benzamide;andN-[3-(3,5-Dimethyl-isoxazole-4-sulfonyl)-5-phenyl-4,5,6,7-tetrahydro-3H-benzoimidazol-5-ylmethyl]-2-methoxy-benzamide

Compound 1: Compound 1 was synthesized as described in example 25.

Compounds 2 and 3: To a solution of 1 (22 mg, 0.061 mmol) in CH₂Cl₂ (0.2mL) was added triethylamine (0.017 mL, 0.12 mmol) followed by3,5-dimethylisoxazole-4-sulfonyl chloride (11.9 mg, 0.061 mmol) and thereaction stirred for 1 hour. Volatiles were removed under stream ofnitrogen and the residue purified by prep TLC eluted with 5/45/50MeOH/EtOAc/CH₂Cl₂ to give the less polar diastereomer 2 (3.5 mg, 11%yield) and more polar diastereomer 3 (7.5 mg, 23% yield) as whitesolids. Rt of 2 and 3 was 1.76 and 1.74 min respectively, usingPhenomenex 30×4.6 5u column with flow rate of 5 mL/min over 2 mingradient. 0 to 100% B. Solvent A=10/90/0.1% MeOH/H2O/TFA. SolventB=90/10/0.1%. [M+H]=521 for both 2 and 3.

Examples 28 and 29

Examples 28 and 29 were synthesized using methodology described inexamples 26 and 27. Ex Structure Name M + H 28

N-[3-(5-Chloro-3-methyl-1H-pyrazole-4-sulfonyl)-5-phenyl-4,5,6,7-tetrahydro-3H-benzoimidazol-5-ylmethyl]-2-ethoxy-benzamide 555 29

N-[1-(5-Chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl)-5-phenyl-4,5,6,7-tetrahydro-1H-benzoimidazol-5-ylmethyl]-2-methoxy- benzamide 555

Example 30N-(2-Amino-6-phenyl-4,5,6,7-tetrahydro-benzothiazol-6-ylmethyl)-2-methoxy-benzamide

Compound 1: The synthesis of compound 1 is described in example 1.

Compound 2: To a solution of 1 (54 mg, 0.16 mmol) in AcOH (0.25 mL) at60° C. was added Br₂ (26 mg, 0.16 mmol), the reaction stirred for 1hour, then thiourea (24 mg, 0.32 mmol) added and the reaction heated atreflux for 1 hour. The solution was cooled to room temperature then thesolvent removed under a stream of nitrogen. The residue was purified byprep TLC eluted with 1/5/94 AcOH/MeOH/CHCl₃ to give 2 (3.5 mg, 11%yield) as a white solid. Rt=1.40 min using Phenomenex 30×4.6 5u columnwith flow rate of 5 mL/min over 2 min gradient. 0 to 100% B. SolventA=10/90/0.1% MeOH/H₂O/TFA. Solvent B=90/10/0.1%. M+H=394.

Example 31N-(2-Acetylamino-6-phenyl-4,5,6,7-tetrahydro-benzothiazol-6-ylmethyl)-2-methoxy-benzamide

Compound 1: The synthesis of compound 1 is described in example 30.

Compound 2: To a vial charged with 1 (10 mg, 0.025 mmol) was addedacetic anhydride (0.10 mL) and the reaction placed in an oil-bath at 60°C. for 0.5 hours. The reaction was cooled to room temperature, ice (1 g)added and the reaction extracted with CHCl₃ (3×1 mL). The organics weredried (Na₂SO₄), filtered and concentrated in vacuo. The residue waspurified on silica gel gradiently eluted with 0 to 100% EtOAc/hexanes togive 2 (8.9 mg, 80% yield) as a white solid. Rt=1.64 min usingPhenomenex 30×4.6 5u column with flow rate of 5 mL/min over 2 mingradient. 0 to 100% B. Solvent A=10/90/0.1% MeOH/H₂O/TFA. SolventB=90/10/0.1%. [M+H]=436.

Example 32N-(2-Diacetylamino-6-phenyl-4,5,6,7-tetrahydro-benzothiazol-6-ylmethyl)-2-methoxy-benzamide

Compound 1: The synthesis of compound 1 is described in example 30.

Compound 2: To a vial charged with 1 (10 mg, 0.025 mmol) was addedacetic anhydride (0.10 mL) and the reaction placed in an oil-bath at160° C. for 0.5 hours. The reaction was cooled to room temperature, ice(1 g) added and the reaction extracted with CHCl₃ (3×1 mL). The organicswere dried (Na₂SO₄), filtered and concentrated in vacuo. The residue waspurified on silica gel gradiently eluted with 0 to 100% EtOAc/hexanes togive 2 (3.8 mg, 32% yield) as a white solid. Rt=1.67 min usingPhenomenex 30×4.6 5u column with flow rate of 5 mL/min over 2 mingradient. 0 to 100% B. Solvent A=10/90/0.1% MeOH/H₂O/TFA. SolventB=90/10/0.1%. [M+H]=478.

Example 332-Methoxy-N-(3-methyl-5-phenyl-4,5,6,7-tetrahydro-1H-indazol-5-ylmethyl)-benzamide

Compound 1: The synthesis of 1 is described in example 1.

Compound 2: To a solution of 1 (426 mg, 1.26 mmol) in TBF (6 mL) at −78°C. was added dropwise a 1.8 M solution of LDA in THF (1.54 mL, 2.78mmol) and the reaction stirred for 1 hour, then pyruvonitrile (0.208 mL,2.78 mmol) was added dropwise and the reaction was stirred for 15minutes turning homogeneous. The reaction was quenched by the additionof satd. NH₄Cl (10 mL), the layers separated, and the aqueous extracedwith Et₂O (3×10 mL). The combined organics were dried (MgSO₄), filteredand concentrated in vacuo. The residue was purified on silica gelgradiently eluted with 20 to 40% EtOAc/hexanes to give 2 (230 mg, 48%yield) as an off-white solid. Rt=1.71 min using Phenomenex 30×4.6 5ucolumn with flow rate of 5 mL/min over 2 min gradient. 0 to 100% B.Solvent A=10/90/0.1% MeOH/H2O/TFA. Solvent B=90/10/0.1%. [M+H]=380.

Compound 3: To a vial charged with 2 (20 mg, 0.053 mmol) in MeOH (0.3mL) was added hydrazine (0.002 mL, 0.06 mmol) and the reaction stirredfor 1 hour then volatiles removed under stream of nitrogen. The residuewas purified on silica gel gradiently eluted with 75 to 100%EtOAc/hexanes to give 3 (10 mg, 50% yield) as a white solid. Rt=1.43 minusing Phenomenex 30×4.6 5u column with flow rate of 5 mL/min over 2 mingradient. 0 to 100% B. Solvent A=10/90/0.1% MeOH/H2O/TFA. SolventB=90/10/0.1%. [M+H]=376.

Examples 34 and 352-Methoxy-N-(3-methyl-5-phenyl-4,5,6,7-tetrahydro-benzo[d]isoxazol-5-ylmethyl)-benzamide; and2-Methoxy-N-(3-methyl-5-phenyl-4,5,6,7-tetrahydro-benzo[c]isoxazol-5-ylmethyl)-benzamide

Compound 1: The synthesis of 1 was described in example 33.

Compounds 2 and 3: To a solution of 1 (20 mg, 0.054 mmol) in hottert-butanol (0.75 mL) was hydroxylamine hydrochloride (4.1 mg, 0.060mmol) and the reaction heated at reflux for 1.5 hours. The solution wascooled to room temperature then the solvent removed under a stream ofnitrogen. The residue was purified by prep HPLC (Rt for 2 and 3=2.25 and2.48 min, respectively) using a YMC S5 ODS 30×100 mm column (YMC, Kyoto,Japan, available from Waters, Milford, Mass.) with flow rate of 40mL/min over 12 min gradient. 55 to 65% B. Solvent A=10/90/0.1%MeOH/H2O/TFA. Solvent B=90/10/0.1%) to give 2 (9.7 mg, 50% yield) and 3(4.8 mg, 25% yield) as a white solids.

Example 362-Methoxy-N-(3-oxo-5-phenyl-2,3,4,5,6,7-hexahydro-1H-indazol-5-ylmethyl)-benzamide

Compound 1: The synthesis of 1 was described in example 1.

Compound 2: To a solution of 1 (473 mg, 1.40 mmol) in THF (6.5 mL) at−78° C. was added dropwise a 1.8 M solution of LDA in THF (1.71 mL, 3.08mmol) and the reaction stirred for 1 hour, then methylcyanoformate(0.244 mL, 3.08 mmol) added dropwise and the reaction was stirred for 1hour. The reaction was quenched by the addition of satd NH₄Cl (10 mL),the layers separated, and the aqueous extracted with Et₂O (3×10 mL). Thecombined organics were dried (MgSO₄), filtered and concentrated invacuo. The residue was purified on silica gel gradiently eluted with 20to 30% EtOAc/hexanes to give 2 (153 mg, 28% yield) as an off-whitesolid. Rt=1.83 min using Phenomenex 30×4.6 5u column with flow rate of 5mL/min over 2 min gradient. 0 to 100% B. Solvent A=10/90/0.1%MeOH/H2O/TFA. Solvent B=90/10/0.1%. [M+H]=396.

Compound 3: To a solution of 2 (12 mg, 0.030 mmol) in MeOH (0.2 mL) wasadded hydrazine (0.001 mL, 0.033 mmol) and the reaction stirred for 3.5hours then volatiles removed under stream of nitrogen. The residue waspurified by prep TLC eluted with 5% MeOH/CH₂Cl₂ to give 3 (6 mg, 50%yield) as a white solid. Rt=1.41 min using Phenomenex 30×4.6 5u columnwith flow rate of 5 mL/min over 2 min gradient. 0 to 100% B. SolventA=10/90/0.1% MeOH/H₂O/TFA. Solvent B=90/10/0.1%. [M+H]=378.

Example 37 2-Methoxy-N-(3-oxo-5-phenyl-1,3,4,5,6,7-hexahydro-benzo[c]isoxazol-5-ylmethyl)-benzamide

Compound 1: The synthesis of 1 was described in example 36.

Compound 2: To a vial charged with hydroxylamine hydrochloride (5.7 mg,0.082 mmol) and sodium acetate trihydrate (1.8 mg, 0.013 mmol) was addeda solution of 1 (17 mg, 0.043 mmol) in EtOH (0.3 mL) and the reactionheated at 80° C. for 4 hours. The reaction was cooled to roomtemperature, volatiles removed under stream of nitrogen, then theresidue was purified on silica gel gradiently eluted with 1 to 10%MeOH/CH₂Cl₂ to give 2 (14 mg, 80% yield) as a white solid. Rt=1.53 minusing Phenomenex 30×4.6 5u column with flow rate of 5 mL/min over 2 mingradient. 0 to 100% B. Solvent A=10/90/0.1% MeOH/H2O/TFA. SolventB=90/10/0.1%. [M+H]=379.

Example 382-Methoxy-N-(1-methyl-3-oxo-5-phenyl-1,3,4,5,6,7-hexahydro-benzo[c]isoxazol-5-ylmethyl)-benzamide

Compound 1: The synthesis of 1 was described in example 36.

Compound 2: To a solution of 1 (17 mg, 0.043 mmol) in EtOH (0.20 mL) wasadded N-methylhydroxylamine hydrochloride (3.6 mg, 0.043 mmol) and thereaction heated at 80° C. for 9 hours. The reaction was cooled to roomtemperature, volatiles removed under stream of nitrogen, then theresidue was purified on silica gel gradiently eluted with 1 to 3%MeOH/CH₂Cl₂ to give 2 (14 mg, 80% yield) as a clear glass. Rt=1.49 minusing Phenomenex 30×4.6 5u column with flow rate of 5 mL/min over 2 mingradient. 0 to 100% B. Solvent A=10/90/0.1% MeOH/H2O/TFA. SolventB=90/10/0.1%. [M+H]=393.

Example 392-Methoxy-N-(6-phenyl-4,5,6,7-tetrahydro-benzo[1,2,3]thiadiazol-6-ylmethyl)-benzamide

Compound 1: The synthesis of 1 was described in example 1.

Compound 2: To a solution of 1 (75 mg, 0.22 mmol) in MeOH (0.75 mL) wasadded p-toluenesulfonylhydrazide (41 mg, 0.22 mmol) then the reactionheated at reflux for 4 hours. The reaction was cooled to roomtemperature then volatiles removed under a stream of nitrogen and thesolid place under high vacuum to leave 2 (110 mg, >95% yield) as a whitesolid. Rt=1.78 mmn using Phenomenex 30×4.6 5u column with flow rate of 5mL/min over 2 min gradient. 0 to 100% B. Solvent A=10/90/0.1%MeOH/H₂O/TFA. Solvent B=90/10/0.1%. [M+H]=506

Compound 3: A vial charged with 2 (60 mg, 0.12 mmol) in CH₂Cl₂ (1 mL)was added thionyl chloride (0.17 mL, 2.4 mmol) and the reaction stirredfor 15 hours. Volatiles were removed under a stream of nitrogen and theresidue purified by silica gel chromatography, eluted with 50%EtOAc/hexanes, to give 3 (43 mg, 85% yield) as a pale yellow oil.Rt=1.63 mmn using Phenomenex 30×4.6 5u column with flow rate of 5 mL/minover 2 min gradient. 0 to 100% B. Solvent A=10/90/0.1% MeOH/H₂O/TFA.SolventB=90/10/0.1%. [M+H]=380.

Example 40 Racemic2-Methoxy-N-(6-phenyl-4,5,6,7-tetrahydro-1H-indazol-6-ylmethyl)-benzamide

Compound 1: Compound 1 is commercially available from Aldrich.

Compound 2: To a solution of phenylmagnesium bromide in THF (1.0 M, 77mL, 77 mmol) cooled in an ice-bath was added a solution of3-ethoxy-2-cylohexen-1-one (10 g, 71 mmol) in THF (7 mL) dropwise viacannula. The reaction was stirred at room temperature for one hour thendecomposed by the addition of 10% H₂SO_(4(aq)) (35 mL) while beingcooled. The THF was removed using rotary evaporation, then the residualaqueous solution was diluted with H₂O (50 mL) and extracted with toluene(3×1 00 mL). The organics were washed with 10% NaOH (aq) (50 mL) and H₂O(50 mL), dried (MgSO₄), filtered and solvent removed. The residue wasdistilled at 138 to 140° C. (1 mm Hg) to give 2 (11.9 g, 98% yield) as apale yellow oil which solidified upon standing.

Compound 3: To a solution of 2 (5.8 g, 33 mmol) in DMF (110 mL) wasadded sodium cyanide (3.3 g, 67 mmol) followed by trimethylaminehydrochloride (4.8 g, 50 mmol) and H₂O (20 mL) then the reaction heatedat 90° C. for 6 h. Solvents were removed by rotary evaporation then H₂O(50 mL) added to the residue and the aqueous solution extracted withtoluene (3×100 mL). The organics were washed with H₂O (50 mL), 10% HCl(aq) (50 mL) and H₂O (50 mL), dried (MgSO₄), filtered and solventremoved. The residue was distilled at 148° C. (1 mm Hg) to give 3 (5.2g, 79% yield) as a viscous pale yellow oil.

Compound 4: To a solution of 3 (2.8 g, 14 mmol) in toluene (40 mL) wasadded ethylene glycol (8.8 mL, 140 mmol) followed byp-toluenesulfonicacid (150 mg (0.8 mmol) and the reaction heated at reflux withazeotropic removal of water using a Dean-Stark trap for 18 hours. Thereaction was cooled to room temperature then poured into satd Na₂CO₃ (30mL) and extracted with Et₂O (3×30 mL), dried (MgSO₄), filtered andsolvent removed. The residue was purified by silica gel chromatography,eluted with 10 to 20% EtOAc/hexanes to give 4 (3.0 g, 90% yield) as awhite solid. ¹H NMR (CDCl₃, 400 mHz) δ 1.59 (m, 1H), 1.78 (m, 1H), 1.96(m, 3H), 2.13 (m, 1H), 2.26 (m, 2H), 3.96 (m, 2H), 4.10 (m, 2H), 7.35(t, 1H, J=8.0 Hz), 7.40 (t, 2H, J=8.0 Hz), 7.51 (d, 2H, J=8.0 Hz).

Compound 5: To a solution of 4 (3.0 g, 12 mmol) in THF (25 mL) was addeda 1.0 M solution of LAH in THF (15 mL, 15 mmol) and the reaction washeated at reflux for 2 hours. The reaction was cooled in an ice-baththen slowly quenched by dropwise addition of 4N NaOH (aq) (1 ml),filtered through a pad of Na₂SO₄, then volatiles removed to leave theamine 5 (3.0 g, quantitative yield) as a clear oil. The material wasused without further purification.

Compound 6: To a solution of 5 (2.0 g 80 mmol) in dichloromethane (35mL) at ice-bath temperature was added triethylamine (2.0 mL, 14 mmol)followed by o-anisoyl chloride (1.6 mL, 11 mmol) and the reactionstirred for 2 hours. The reaction was diluted with Et₂O (75 mL) thenwashed with satd Na₂CO₃ (25 mL) and solvent evaporated. The residue wasbrought up into THF (50 mL) then 2N HCl (aq) (17 mL) added and thereaction heated at 40° C. for 3 hours. The reaction was cooled, pouredinto Et₂O (75 mL) and washed with satd Na₂CO₃ (30 mL). The organic layerwas dried (MgSO₄), filtered and solvent removed and residue was purifiedby silica gel chromatography, eluted with 10 to 70% EtOAc/hexanes, togive 6 (2.3 g, 83% yield) as a white solid. [M+H]=338.

Compound 7: To a flask charged with 6 (300 mg, 0.90 mmol) was added a1.0 M solution of potassium tert-butoxide in tert-butanol (3.3 mL, 3.3mmol) and the reaction stirred for 15 minutes, then ethyl formate (0.26mL, 3.3 mmol) was added dropwise (gas evolution) and the reactionstirred for 1 hour. The reaction was quenched by the addition of satdNH₄Cl (15 mL) then extracted with CH₂Cl₂ (20 ml). The organic layer waswashed with brine (10 mL), dried (Na₂SO₄), filtered, and concentrated invacuo to provide 7 as a sticky white solid (320 mg, >95%), which wasused in the following reaction without further purification.

Compound 8: To a solution of 7 (95 mg, 0.26 mmol) in MeOH (2 mL) wasadded hydrazine monohydrate (0.013 mL, 0.26 mmol) and the reactionstirred for 18 hours. Volatiles were removed under a stream of nitrogenthen the residue purified by prep HPLC (Rt-17.8 min using PhenomenexLuna 5u C18 30×250 mm column with flow rate of 30 ml/min over 20 mingradient. 20 to 100% Solvent B. Solvent A=10/90/0.1% MeOH/H2O/TFA.Solvent B=90/10/0.1%.) to give 8 (93 mg, 100% yield) as a clearcolorless glass. ¹H NMR (CDCl₃, 400 mHz) δ 2.14 (m, 1H), 2.32 (m, 2H),2.73 (m, 1H), 3.03 (d, 1H, J=18.0 Hz), 3.49 (d, 1H, J=18.0 Hz), 3.58 (s,3H), 3.74 (dd, 1H, J=4.8, 13.6 Hz), 3.99 (dd, 1H, J=7.0, 13.6 Hz), 6.87(d, 1H, 8.4 Hz), 7.04 (t, 1H, 7.5 Hz), 7.29-7.44 (m, 6H), 7.53 (s, 1H),7.80 (bt, 1H), 8.13 (d, 1H, J=9.2 Hz), 11.0 (bs, 1H).

Example 41

Example 41 was synthesized using methodology described in example 40. ExStructure Name M + H 41

2-Methoxy-N-(2-methyl-6-phenyl-4,5,6,7-tetrahydro-2H-indazol-6-ylmethyl)-benzamide 376

Example 422-Methoxy-N-(6-phenyl-4,5,6,7-tetrahydro-benzo[d]isoxazol-6-ylmethyl)-benzamide

Compound 1: Compound 1 was synthesized as described in example 40.

Compound 2: To a solution of 1 (80 mg, 0.22 mmol) in hot tert-butanol (4mL) was added hydroxylamine hydrochloride (18 mg, 0.25 mmol) and thereaction heated at reflux for 1.5 hours. The reaction was cooled andvolatiles removed on rotary evaporator. The residue was purified by prepHPLC (Rt=7.00 min using YMC S5 ODS 30×100 mm column with flow rate of 40ml/min over 10 min gradient. 40 to 100% Solvent B. Solvent A=10/90/0.1%MeOH/H2O/TFA. Solvent B=90/10/0.1%.) to give 2 (50 mg, 63% yield) as aclear colorless oil. M+H=363.

Example 432-Methoxy-N-(6-phenyl-4,5,6,7-tetrahydro-benzo[c]isoxazol-6-ylmethyl)-benzamide

Compound 1: Compound 1 was synthesized as described in example 40.

Compound 2: To a solution of 1 (80 mg, 0.22 mmol) in pyridine (4 mL) wasadded a solution of hydroxylamine hydrochloride (38 mg, 0.55 mmol) inH₂O (0.20 mL) and the reaction heated at reflux for 5 hours. Thereaction was cooled and volatiles removed on rotary evaporator. Theresidue was purified by prep HPLC (Rt=6.57 min using YMC S5 ODS 30×100mm column with flow rate of 40 ml/min over 10 min gradient. 40 to 100%Solvent B. Solvent A=10/90/0.1% MeOH/H₂O/TFA. Solvent B=90/10/0.1%.) togive 2 (49 mg, 61% yield) as a clear colorless oil. M+H=363.

Example 442-Methoxy-N-(3-phenyl-2,3,4,9-tetrahydro-1H-carbazol-3-ylmethyl)-benzamide

Compound 1: Compound 1 is was synthesized as described in example 1.

Compound 2: To a solution of 1 (90 mg, 0.27 mmol) in acetic acid (2 mL)was added a solution of phenylhydrazine (0.026 mL, 0.27 mmol) in aceticacid (1 mL) and the mixture heated at 50° C. for 1 hour. The reactionwas cooled to room temperature then boron trifluoride etherate (0.060mL, 0.46 mmol) added and the reaction heated at 80° C. for 16 hours. Themixture was diluted with CH₂Cl₂ (25 mL) and washed with satd NaHCO₃(3×15 mL, caution: vigorous gas evolution). The organic layer was dried(Na₂SO₄), filtered, and concentrated in vacuo. The residue waschromatographed on silica gel, eluted with 40% EtOAc/hexanes, to give 2(87 mg, 78% yield) as an off-white solid. Rt=1.96 min using Phenomenex30×4.6 5u column with flow rate of 5 mL/min over 2 min gradient. 0 to100% B. Solvent A=10/90/0.1% MeOH/H2O/TFA. Solvent B=90/10/0.1%.[M+H]=411.

Example 45

Example 45 was synthesized using methodology described in example 44. ExStructure Name M + H 45

2-Methoxy-N-(9-methyl-3-phenyl-2,3,4,9-tetrahydro-1H-carbazol-3-ylmethyl)-benzamide 425

Examples 46 to 492-Methoxy-N-(((6S,7aS)-3-methoxy-6-phenyl-3a,4,5,6,7,7a-hexahydrobenzo[d]isoxazol-6-yl)methyl)benzamide;2-Methoxy-N-(((3aS,5S)-3-methoxy-5-phenyl-3a,4,5,6,7,7a-hexahydrobenzo[d]isoxazol-5-yl)methyl)benzamide;2-Methoxy-N-(((3aS,5R)-3-methoxy-5-phenyl-3a,4,5,6,7,7a-hexahydrobenzo[d]isoxazol-5-yl)methyl)benzamide;2-Methoxy-N-(((6R,7aS)-3-methoxy-6-phenyl-3a,4,5,6,7,7a-hexahydrobenzo[d]isoxazol-6-yl)methyl)benzamide

Compound 1: Compound 1 is commercially available.

Compound 2: To a hot solution (110° C.) of Red-Al® (35 mL, 110 mmol) intoluene (150 mL) under a nitrogen atmosphere, solid4-phenyl-4-cyano-cyclohexane-1-one 1 (10 g, 50 mmol) was added in smallportions over 30 minutes. Heating was continued for an additional 30minutes, the reaction was cooled, excess Red-Ale was decomposed bycareful addition of 50% THF-water, and the reaction was digested byportion wise addition of water until a white paste precipitated. Theclear supernatant was decanted, the solvent removed under reducedpressure and the residue was flash chromatographed through ammoniatreated silica eluting with 25% methanol-methylene chloride providing 2(8.89 g, 87%) as a yellow solid which was used without furthertreatment.

Compound 3: To a cold (0° C.) solution of 3 (20.85 g, 102 mmol) indichloromethane (200 mL) and triethylamine (14.1 mL, 102 mmol) anisoylchloride was added drop wise and stirred at room temperature for 2hours. The reaction mixture was washed with two portions of 1 N HCl,dried over magnesium sulfate and the solvent was removed under reducedpressure. The residue was suspended in ethyl acetate, the resultingwhite solid collected by filtration affording 3 (21.11 g, 51.8%). LC-MS[M+H]=340

Compound 4: To cold suspension (0° C.) of 3 (21 g, 62 mmol) in pyridine(49 mL), toluenesulfonyl chloride (13 g, 68 mmol) was added and themixture was left to stand for four days. The resulting solid mass waspartitioned between methylene chloride and dilute HCl, the organic layerwas washed with one portion of dilute HCl, dried over magnesium sulfate,the solvent removed under reduced pressure and the resulting solid waswashed by suspension in methanol providing 4 (22.97 g, 75%) as a whitepowder. LC-MS [M+H]=493.

Compound 5: A mixture of 4 (20 g, 40 mmol) and DBU (18.5 g, 120 mmol) intoluene (300 mL) was heated at reflux for 6 hours, cooled, washed with asaturated aqueous solution of sodium bicarbonate, dried over magnesiumsulfate and the solvent was removed under reduced pressure. The residueflash chromatographed eluting with 5% ethyl acetate-methylene chlorideafforded 5 (9.82 g, 76%) as a white solid. [M+H]=322

Compound 6: A mixture of phenylsulfonyl acetic acid (12 g, 60 mmol) andnitric acid (18 mL, >90%) in acetic acid (36 mL) was heated at refluxfor 1.5 hours, cooled, poured over ice and the solid was collected byfiltration. Recrystallization from isopropanol afforded 6 (4.78 g, 44%)as a white solid.

Compounds 7-10: A mixture of 5 (1 g, 3.1 mmol)and 6 (0.8 g, 2.4 mmol} inTHF (2 mL) was heated in a microwave reactor (180° C. 10 min.), thesolvent was removed under reduced pressure (LC-MS [M+H]=505) and theisomers were separated by silica gel chromatography (25% ethylacetate-methylene chloride) without structural assignment. Fraction 1(311 mg), fraction 2 (318 mg), fraction 3 (168 mg), fraction 4 (222 mg).Each of the individual fractions were dissolved in MeOH (0.2M) andpotassium carbonate (6 eq) added then the reaction heated in a microwavereactor (130° C., 10 min.). The potassium carbonate was removed byfiltration, the solvent was removed under reduced pressure and theresidue was purified by flash chromatography eluting with 10%methanol-methylene chloride affording 7, 8, 9, and 10 (50-80% yield,2-steps) as white solids. [M+H]=395. Structural assignment wasdetermined by nOE NMR experiments.

Example 50 RacemicN-(2-Amino-6-phenyl-5,6,7,8-tetrahydro-quinazolin-6-ylmethyl)-2-methoxy-benzamide

Compound 1: Compound 1 was synthesized as described in example 1.

Compound 2: To a solution of sodium ethoxide (4.3 mg 0.063 mmol) inethanol (0.5 mL) was added guanidine hydrochloride (6.1 mg, 0.063 mmol)and the mixture stirred for 0.5 hours, then a solution of 1 (25 mg,0.063 mmol) in ethanol (0.5 mL) was added and the reaction heated atreflux for 3 h. Volatiles were removed under a stream of nitrogen thenthe residue chromatographed with May 25, 1970 MeOH/hexanes/EtOAc to give2 (10.3 mg, 42% yield) as a white solid. ¹H NMR (CDCl₃, 500 mHz) δ 2.12(m, 11H), 2.35 (m, 2H), 2.71 (m, 1H), 2.86 (d, 1H, J=16.8 Hz), 3.21 (d,1H, J=16.8 Hz), 3.55 (s, 3H), 3.64 (dd, 1H, J=5.0, 13.5 Hz), 3.97 (dd,1H, J=7.4, 13.4 Hz), 4.84 (s, 2H), 6.84 (d, 1H, J=8.8 Hz), 7.05 (t, 1H,J=7.4 Hz), 7.26(m, 1H), 7.34 (m, 4H), 7.39 (m, 1H), 7.66 (bt, 1H), 8.08(s, 1H), 8.19 (dd, 1H, J=1.6, 8.0 Hz). Rt=1.35 min using a Phenomenex30×4.6 5u column with flow rate of 5 mL/min over 2 min gradient. 0 to100% B. Solvent A=10/90/0.1% MeOH/H2O/TFA. Solvent B=90/10/0.1%.[M+H]=389.

Examples 51 to 54

Examples 51 to 54 were synthesized using methodology described inexample 1. Ex Structure Name M + H 51

2-Methoxy-N-(2-methyl-6-phenyl-5,6,7,8-tetrahydro-quinazolin-6-ylmethyl)-benzamide 388 52

N-(2-tert-Butyl-6-phenyl-5,6,7,8-tetrahydro-quinazolin-6-ylmethyl)-2-methoxy-benzamide 431 53

2-Methoxy-N-(2-methylsulfanyl-6-phenyl-5,6,7,8-tetrahydro-quinazolin-6-ylmethyl)-benzamide 421 54

2-Methoxy-N-(2-methoxy-6-phenyl-5,6,7,8-tetrahydro-quinazolin-6-ylmethyl)-benzamide 404 55

2-Methoxy-N-(6-phenyl-5,6,7,8-tetrahydro-quinazolin-6-ylmethyl)-benzamide 374

Examples 56 and 57 Enantiomerically pureN-(2-Dimethylamino-6-phenyl-5,6,7,8-tetrahydro-quinazolin-6-ylmethyl)-2-methoxy-benzamide

Compound 1: Compound 1 was synthesized as described in example 1.

Compounds 2 and 3: To a suspension of 1 (485 mg, 1.44 mmol) indimethylformamide (0.20 mL) was added N,N-dimethylformamidedimethylacetal (0.21 mL, 1.58 mmol) and the reaction heated at 110° C.for 24 hours. The solution was cooled to room temperature then dilutedethanol (1 mL). This solution was added to a mixture of(S)-(+)-α-(methoxymethyl)phenethylamine hydrochloride (320 mg, 1.58mmol) and sodium ethoxide (108 mg, 1.58 mmol), which had been prestirredfor 0.5 hours, then the reaction heated at 40° C. for 16 hours. Thereaction was cooled to room temperature, volatiles removed under astream of nitrogen, then the residue chromatographed on silica gelelution with 3/47/50 MeOH/EtOAc/hexanes to give the less polardiastereomer 2 (132 mg, 18% yield) and more polar diastereomer 3 (207mg, 28% yield) as white solids. Rt of 2 and 3 was 1.71 and 1.69 min,respectively, using a Phenomenex 30×4.6 5u column with flow rate of 5mL/min over 2 min gradient. 0 to 100% B. Solvent A=10/90/0.1%MeOH/H2O/TFA. Solvent B=90/10/0.1%.

Compound 4: To a vial charged with 1,1-dimethylguanidine sulfate (33 mg,0.12 mmol) was added a solution of sodium ethoxide (8.2 mg, 0.12 mmol)in ethanol (0.5 mL) and the mixture stirred for 0.5 hours then asolution of 2 (61 mg, 0.12 mmol) in ethanol (1 mL) added. The vial wassealed then heated in an oil-bath at 100° C. for 40 hours then heated at190° C. (in microwave) for 1 hour. The reaction was cooled to roomtemperature, volatiles removed under a stream of nitrogen, and theresidue purified by prep TLC, eluted with 2/28/70 MeOH/EtOAC/hexanes, togive 4 (30 mg, 60% yield) as a white solid. This material was determinedto have 93% ee using a DIACEL OD 4.6×250 mm chiral analytical column(Diacel Chemical Industries, Arai Plant, Niigata, Japan, available fromChiral Technologies, Exton, Pa.) (Rt of 11.8 min) with flow rate of 1mL/min, isocratic elution using 30% isopropyl alcohol/hexanes. Thismaterial was purified to 100% ee using a Chiracel OD 5×50 cm 20u chiralpreparative column (Diacel Chemical Industries, available from ChiralTechnologies, Exton, Pa.), isocratic elution using 30% isopropylalcohol/hexanes, to give 4 (25 mg, 50% yield) as a white solid. M+H=418.

Compound 5: Compound 5 was synthesized starting from 3 on the same scaleand purified in the same manner as 4 to give 5 (30 mg, 0.072 mmol, 60%yield) as a white solid in enantiomerically pure form. Rt of 5 was 10.1min using a DIACEL OD 4.6×250 mm chiral analytical column with flow rateof 1 mL/min, isocratic elution using 30% isopropyl alcohol/hexanes.M+H=418.

Examples 58 and 59 Enantiomerically Enriched2-Methoxy-N-(2-methylamino-6-phenyl-5,6,7,8-tetrahydro-quinazolin-6-ylmethyl)-benzamide

Compound 1: Compound 1 was synthesized as described in example 1.

Compounds 2 and 3: To a solution of 1 (379 mg, 0.97 mmol) in ethanol (1mL) was added (R)-(−)-1-cyclohexylethylamine (0.16 mL, 1.07 mmol) andthe reaction heated at 40° C. for 18 hours. The reaction was cooled toroom temperature, volatiles removed under stream of nitrogen, then theresidue chromatographed on silica gel eluted with 3/40/57MeOH/EtOAc/hexanes to give the less polar diastereomer 2 (116 mg, 25%yield) and more polar diastereomer 3 (117 mg, 25% yield) as yellow oils.

Compound 4: To a solution of 1-methylguanidine hydrochloride (8.2 mg,0.75 mmol) and sodium ethoxide (4.8 mg, 0.75 mmol) in ethanol (0.75 mL)that had been prestirred for 0.5 hours was added a solution of the lesspolar diastereomer 2 (22 mg, 0.046 mmol) in ethanol (0.5 mL), then thereaction microwaved at 180° C. for 2 hours. The reaction was cooled toroom temperature, volatiles removed, and the residue chromatographed onsilica gel eluted with 2/30/68 MeOH/hexanes/EtOAc to give 4 (6.4 mg, 35%yield) as an off-white solid. The material was determined to have 88% eeusing a DIACEL OD 4.6×250 mm chiral analytical column (Rt of 15.4 min)with flow rate of 1 mL/min, isocratic elution using 30% isopropylalcohol/hexanes. M+H=404.

Compound 5: Compound 5 was synthesized starting from 3 on the same scaleand purified in the same manner as 4 to give 5 (6.9 mg, 37% yield) as awhite solid. The material was determined to have 83% ee using a DIACELOD 4.6×250 mm chiral analytical column (Rt of 12.9 min) with flow rateof 1 mL/min, isocratic elution using 30% isopropyl alcohol/hexanes.M+H=404.

Examples 60 to 63

Examples 60 to 63 were synthesized using methodology described inexample 7. Compounds synthesized starting from 2 (examples 11 and 13)were generated in 88% ee. Compounds synthesized starting from 3(examples 12 and 14) were generated in 83% ee. Ex Structure Name M + H60

N-(2-Ethylamino-6-phenyl-5,6,7,8-tetrahydro-quinazolin-6-ylmethyl)-2-methoxy-benzamide 418 61

N-(2-Ethylamino-6-phenyl-5,6,7,8-tetrahydro-quinazolin-6-ylmethyl)-2-methoxy-benzamide 418 62

2-Methoxy-N-(2-morpholin-4-yl-6-phenyl-5,6,7,8-tetrahydro-quinazolin-6-ylmethyl)-benzamide 460 63

2-Methoxy-N-(2-morpholin-4-yl-6-phenyl-5,6,7,8-tetrahydro-quinazolin-6-ylmethyl)-benzamide 460

Example 64 RacemicN-(2-Dimethylamino-4-methyl-6-phenyl-5,6,7,8-tetrahydro-quinazolin-6-ylmethyl)-2-methoxy-benzamide

Compound 1: The synthesis of 1 is described in example 33.

Compound 2: To a vial charged with 1 (20 mg, 0.053 mmol),1,1-dimethylguanidine sulfate (29 mg, 0.11 mmol) and sodium ethoxide(7.2 mg, 0.11 mmol) was added ethanol (0.5 mL). The vial was sealed thenplaced in an 80° C. oil-bath for 2.5 hours, cooled to room temperature,filtered, then volatiles removed under stream of nitrogen. The residuewas purified on silica gel gradiently eluted with 1 to 5% MeOH/CH₂Cl₂ togive 2 (13 mg, 58% yield) as a white solid. Rt=1.48 min using Phenomenex30×4.6 5u column with flow rate of 5 mL/min over 2 min gradient. 0 to100% B. Solvent A=10/90/0.1% MeOH/H2O/TFA. Solvent B=90/10/0.1%.[M+H]=431.

Example 65N-(2-Dimethylamino-4-oxo-6-phenyl-3,4,5,6,7,8-hexahydro-quinazolin-6-ylmethyl)-2-methoxy-benzamide

Compound 1: The synthesis of 1 was described in example 36.

Compound 2: To a vial charged with 1 (19 mg, 0.048 mmol),1,1-dimethylguanidine sulfate (27 mg, 0.10 mmol) and sodium ethoxide(6.8 mg, 0.10 mmol) was added ethanol (1 mL). The vial was sealed thenplaced in an 80° C. oil-bath for 8 hours, cooled to room temperature,filtered, then volatiles removed under stream of nitrogen. The residuewas purified on silica gel gradiently eluted with 1 to 10% MeOH/CH₂Cl₂to give 2 (18 mg, 85% yield) as a white solid. Rt=1.33 min usingPhenomenex 30×4.6 5u column with flow rate of 5 mL/min over 2 mingradient. 0 to 100% B. Solvent A=10/90/0.1% MeOH/H2O/TFA. SolventB=90/10/0.1%. [M+H]=433.

Example 66 Racemic2-Methoxy-N-(6-phenyl-5,6,7,8-tetrahydro-quinolin-6-ylmethyl)-benzamide

Compound 1: The synthesis of 1 was described in example 1.

Compound 2: To a vial charged with 1 (50 mg, 0.15 mmol) was added sodiumacetate trihydrate (52 mg, 0.41 mmol) and o-allylhydroxylaminehydrochloride (26 mg, 0.24 mmol) followed by ethanol (0.5 mL). The vialwas sealed an the reaction heated in an 80° C. oil-bath for 2 hours. Thereaction was cooled to room temperature, diluted with chloroform (10 mL)and extraced with H₂O (3×10 mL). The organic layer was dried (MgSO₄),filtered and concentrated in vacuo to give 2 (56 mg, 95% yield) as awhite solid. Rt=1.91 min using Phenomenex 30×4.6 5u column with flowrate of 5 mL/min over 2 min gradient. 0 to 100% B. Solvent A=10/90/0.1%MeOH/H₂O/TFA. Solvent B=90/10/0.1%. [M+H]=393.

Compound 3: A vial charged with 2 (30 mg, 0.075 mmol) was sealed underair and heated in an 180° C. oil-bath for 40 hours. The residue waspurified on silica gel eluted with 5% MeOH/CH₂Cl₂ to give 3 (2.6 mg, 10%yield) as a white solid. Rt=1.29 min using Phenomenex 30×4.6 5u columnwith flow rate of 5 mL/min over 2 min gradient. 0 to 100% B. SolventA=10/90/0.1% MeOH/H2O/TFA. Solvent B=90/10/0.1%. [M+H]=373.

Publications and references, including but not limited to patents andpatent applications, cited in this specification are herein incorporatedby reference in their entirety in the entire portion cited as if eachindividual publication or reference were specifically and individuallyindicated to be incorporated by reference herein as being fully setforth. Any patent application to which this application claims priorityis also incorporated by reference herein in the manner described abovefor publications and references.

While this invention has been described with an emphasis upon preferredembodiments, it will be obvious to those of ordinary skill in the artthat variations in the preferred devices and methods may be used andthat it is intended that the invention may be practiced otherwise thanas specifically described herein. Accordingly, this invention includesall modifications encompassed within the spirit and scope of theinvention as defined by the claims that follow.

1. A compound of formula I

wherein, n and m are integers such that ring H, including its fusion partner, is a 5 to 7 membered ring; A, B, D and E are —CR⁶═, —CR⁶—, —C(═O)—, —NR⁷—, —N═, —O—, —S—, a bond, or a double bond, such that ring G, including atoms shared with its fusion partner, is a 5 to 6 membered ring, ring G is a heterocycle wherein at least one ring atom is nitrogen, and ring G and —C(═O)—, if present, contains at least one unsaturated bond; R¹ is aryl, which ring can be substituted with one or more groups of the formula —(CH₂)_(p)-(Z¹)_(q)—(CH₂)_(r)—Z²; R² is aryl, heteroaryl, cycloalkyl or heterocyclo, which ring structures can be substituted with one or more groups of the formula —(CH₂)_(p)-(Z¹)_(q)—(CH₂)_(r)-Z², which substituents may, in one or more pairs of two, together with the atoms to which they are bonded, form a carbocyclic, substituted carbocyclic, heterocyclic or substituted heterocyclic group; Y is —C(═O), —C(═S)—, C(═NR⁹)—, —C(═NR¹⁰)NR¹¹—, —C(═O)—O—, —C(═S)—O—, —C(═NR¹²), —SO₂—, —SO₂—, or a single bond; R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are the same or different and are independently selected from groups of the formula —(CH₂)_(p)-(Z¹)_(q)—(CH₂)_(r)-Z²; or R³, R⁴ and R⁵ may, in one or more pairs of two (such as R⁵ and R³, R² and R³, R³ and R⁴ or R⁴ and R⁵), together with the atoms to which they are bonded, form a carbocyclic, substituted carbocyclic, heterocyclic or substituted heterocyclic group; or R⁶ and R⁷ may, in one or more pairs of two, may, together with the atoms to which they are bonded, form a carbocyclic, substituted carbocyclic, heterocyclic or substituted heterocyclic group; or two occurrences of R⁶ (R⁶ and R⁶*) may, together with the atoms to which they are bonded, form a phenyl, which may be substituted; Z¹ is —CZ³Z⁴-, —O—, —NZ⁵-, —S—, —SO—, —SO₂—, —C(O)—, —C(O)Z⁶-, —C(O)NZ⁷-, —C(S)—, —C(═NOZ⁸)-, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carbocyclo, substituted carbocyclo, aryl, substituted aryl, heterocyclo, or substituted heterocyclo; Z² is hydrogen, —OZ⁹, —OC(O)Z¹⁰, —NZ¹¹-C(O)-Z¹², —NZ¹³-CO₂-Z¹⁴, —NZ¹⁵(C═O)—NZ¹⁶Z¹⁷, —NZ¹⁸Z¹⁹, —NO₂, halo, —CN, —C(O)Z²⁰, —CO₂Z²¹, —C(S)Z²², —(C═NOZ²³)Z²⁴, —C(O)NZ²⁵Z²⁶, —C(S)NZ²⁷Z²⁸, —SZ²⁹, —SOZ³⁰, —SO₂Z³¹, —SO₂NZ³²Z³³, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carbocyclo, substituted carbocyclo, aryl, substituted aryl, heterocyclo (such as heteroaryl), or substituted heterocyclo, or Z² together with Z⁵ may together with a nitrogen to which they are bonded, form a carbocyclic, substituted carbocyclic, heterocyclic or substituted heterocyclic group; Z⁵ is hydrogen, —C(O)Z²⁰, —CO₂Z²¹, —C(S)Z²², —(C═NOZ²³)Z²⁴, —C(O)NZ²⁵Z²⁶, —C(S)NZ 7Z²⁸, —SZ²⁹, —SOZ³⁰, —SO₂Z³¹, —SO₂NZ³²Z³³, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carbocyclo, substituted carbocyclo, aryl, substituted aryl, heterocyclo (such as heteroaryl), or substituted heterocyclo or forms a ring with Z² as specified above; Z³, Z⁴, Z⁶, Z⁷, Z⁸, Z⁹, Z¹⁰, Z¹¹, Z¹², Z¹³, Z¹⁴, Z¹⁵, Z¹⁶, Z¹⁷, Z¹⁸, Z¹⁹, Z²⁰, Z²¹, Z²², Z²³, Z²⁴, Z²⁵, Z²⁶, Z²⁷, Z²⁸, Z²⁹, Z³⁰, Z³¹, Z³² and Z³³ are independently hydrogen, halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carbocyclo, substituted carbocyclo, aryl, substituted aryl, heterocyclo, or substituted heterocyclo; or Z¹³, Z⁴, Z⁶, Z⁷, Z⁸, Z⁹, Z¹⁰, Z¹¹, Z¹², Z¹³, Z¹⁴, Z¹⁵, Z¹⁶, Z¹⁷, Z¹⁸, Z¹⁹, Z²⁰, Z²¹, Z²², Z²³, Z²⁴, Z²⁵ Z²⁶, Z²⁷, Z²⁸, Z²⁹, Z³⁰, Z³¹, Z³² and Z³³ may, in one or more pairs of two, together with the atoms to which they are bonded, form a carbocyclic, substituted carbocyclic, heterocyclic or substituted heterocyclic group; p and r are independently selected from integers from 0 to 10 wherein, when q is 0, r is also 0; and q is an integer selected from 0 or 1, and salts, solvates or prodrugs of the foregoing.
 2. The compound of claim 1, wherein R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are the same or different and are independently selected from groups of the formula —(CH₂)_(p)-(Z¹)_(q)—(CH₂)_(r)-Z²; and one or more of the following pertains: Z¹ is —CZ³Z⁴-, —O—, —NZ⁵-, —S—, —SO—, —SO₂—, —C(O)—, —C(O)Z⁶-, —C(O)NZ⁷-, —C(S)—, —C(═NOZ⁸)-, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl; and/or Z² is hydrogen, —OZ⁹, —OC(O)Z¹⁰, —NZ⁵-C(O)-Z¹¹, —NZ¹²—CO₂-Z¹³, —NZ¹⁴(C═O)—NZ¹⁵Z¹⁶, —NZ¹⁷Z¹⁸, —NO₂, halo, —CN, —C(O)Z¹⁹, —CO₂Z²¹, —C(S)Z²¹, —(C═NOZ²²)Z²³, —C(O)NZ²⁴Z²⁵, —C(S)NZ²⁶Z²⁷, —SZ²⁸, —SOZ²⁹, —SO₂Z³⁰, —SO₂NZ³¹Z³², alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, or, with respect to R⁷ may further be aryl, substituted aryl, heteroaryl or substituted heteroaryl; and/or Z⁵ is hydrogen, —C(O)Z²⁰, —CO₂Z²¹, —C(S)Z²², —(C═NOZ²³)Z²⁴, —C(O)NZ²⁵Z²⁶, —C(S)NZ²⁷Z²⁸, —SZ²⁹, —SOZ³⁰, —SO₂Z³¹, —SO₂NZ³²Z³³, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carbocyclo, substituted carbocyclo, aryl, substituted aryl, heterocyclo (such as heteroaryl), or substituted heterocyclo; and/or Z³, Z⁴, Z⁶, Z⁷, Z⁸, Z⁹, Z¹⁰, Z¹¹, Z¹², Z¹³, Z¹⁴, Z¹⁵, Z¹⁶, Z¹⁷, Z¹⁸, Z¹⁹, Z²⁰, Z²¹, Z²², Z²³, Z²⁴ Z²Z²⁶, Z²⁷, Z²⁸, Z²⁹, Z³⁰, Z³¹, Z³² and Z³³ are independently hydrogen, halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl.
 3. The compound of claim 1, wherein ring H is a six-membered ring.
 4. The compound of claim 3, wherein n=2 and m=1.
 5. The compound of claim 1, wherein ring G is according to one of the following: G A B D E 1 —N═ or —NR⁷ — —N═ or —NR⁷— —CR⁶═ or —CR⁶— bond 2 —CR⁶═ or —CR⁶— —N═ or —NR⁷— —N═ or —NR⁷— bond 3 —N═ or —NR⁷— —CR⁶═ or —CR⁶— —N═ or —NR⁷— bond 4 —O— —N═ or —NR⁷— —CR⁶═ or —CR⁶— bond 5 —N═ or —NR⁷— —O— —CR⁶═ or —CR⁶— bond 6 —O— —NR⁷— —C(═O)— bond 7 —NR⁷— —O— —C(═O)— bond 8 —CR⁶═ or —CR⁶— —N═ or —NR⁷— —O— bond 9 —CR⁶═ or —CR⁶— —O— —N═ or —NR⁷— bond 10 —N═ or —NR⁷— —N═ or —NR⁷— —S— bond 11 —N═ or —NR⁷— —CR⁶═ or —CR⁶— —S— bond 12 —N═ or —NR⁷— —CR⁶═ or —CR⁶— —N═ or —NR⁷— —CR⁶═ or —CR⁶— 13 —N═ or —NR⁷— —CR⁶═ or —CR⁶— —CR⁶═ or —CR⁶— —CR⁶═ or —CR⁶—


6. The compound of claim 1, wherein ring G is according to:


7. The compound of claim 6, wherein R⁶ is hydrogen.
 8. The compound of claim 1, wherein Y comprises carbonyl or thiocarbonyl or a single bond.
 9. The compound of claim 1, wherein Y comprises carbonyl or a single bond.
 10. A compound of claim 1, selected from: 2-Methoxy-N-(5-phenyl-4,5,6,7-tetrahydro-2H-indazol-5-ylmethyl)-benzamide; 2-Methoxy-N-(2-methyl-5-phenyl-4,5,6,7-tetrahydro-2H-indazol-5-ylmethyl)-benzamide; 2-Methoxy-N-(5-phenyl-4,5,6,7-tetrahydro-benzo[d]isoxazol-5-ylmethyl)-benzamide; 2-Methoxy-N-(5-phenyl-4,5,6,7-tetrahydro-benzo[c]isoxazol-5-ylmethyl)-benzamide; N-(1,5-Diphenyl-4,5,6,7-tetrahydro- 1H-indazol-5-ylmethyl)-2-methoxy-benzamide; N-(2,5-Diphenyl-4,5,6,7-tetrahydro-2H-indazol-5-ylmethyl)-2-methoxy-benzamide; N-[1-(2-Hydroxy-ethyl)-5-phenyl-4,5,6,7-tetrahydro-1H-indazol-5-ylmethyl]-2-methoxy-benzamide; N-[2-(2-Hydroxy-ethyl)-5-phenyl-4,5,6,7-tetrahydro-2H-indazol-5-ylmethyl]-2-methoxy-benzamide; N-[1-(6-Chloro-pyridazin-3-yl)-5-phenyl-4,5,6,7-tetrahydro-1H-indazol-5-ylmethyl]-2-methoxy-benzamide; N-[2-(6-Chloro-pyridazin-3-yl)-5-phenyl-4,5,6,7-tetrahydro-2H-indazol-5-ylmethyl]-2-methoxy-benzamide; N-(2-tert-Butyl-5-phenyl-4,5,6,7-tetrahydro-2H-indazol-5-ylmethyl)-2-methoxy-benzamide; N-(1-Benzyl-5-phenyl-4,5,6,7-tetrahydro-1H-indazol-5-ylmethyl)-2-methoxy-benzamide; N-(2-Benzyl-5-phenyl-4,5,6,7-tetrahydro-2H-indazol-5-ylmethyl)-2-methoxy-benzamide; 2-Methoxy-N-[5-phenyl-2-(propane-2-sulfonyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylmethyl]-benzamide; 2-Methoxy-N-[5-phenyl-1-(propane-2-sulfonyl)-4,5,6,7-tetrahydro-1H-indazol-5-ylmethyl]-benzamide; N-(2-Methanesulfonyl-5-phenyl-4,5,6,7-tetrahydro-2H-indazol-5-ylmethyl)-2-methoxy-benzamide; 2-Methoxy-N-[1-(1-methyl-1H-imidazole-4-sulfonyl)-5-phenyl-4,5,6,7-tetrahydro-1H-indazol-5-ylmethyl]-benzamide; 2-Methoxy-N-[2-(1-methyl-1H-imidazole-4-sulfonyl)-5-phenyl-4,5,6,7-tetrahydro-2H-indazol-5-ylmethyl]-benzamide; 2-Methoxy-N-[5-phenyl-2-(2,3,4-trifluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-2H-indazol-5-ylmethyl]-benzamide; 2-Methoxy-N-[5-phenyl-1-(2,3,4-trifluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-1H-indazol-5-ylmethyl]-benzamide; N-[2-(5-Chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl)-5-phenyl-4,5,6,7-tetrahydro-2H-indazol-5-ylmethyl]-2-methoxy-benzamide; N-[1-(5-Chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl)-5-phenyl-4,5,6,7-tetrahydro-1H-indazol-5-ylmethyl]-2-methoxy-benzamide; N-[2-(3,5-Dimethyl-isoxazole-4-sulfonyl)-5-phenyl-4,5,6,7-tetrahydro-2H-indazol-5-ylmethyl]-2-methoxy-benzamide; N-[1-(3,5-Dimethyl-isoxazole-4-sulfonyl)-5-phenyl-4,5,6,7-tetrahydro-1H-indazol-5-ylmethyl]-2-methoxy-benzamide; 2-Methoxy-N-(5-phenyl-4,5,6,7-tetrahydro-1H-benzoimidazol-5-ylmethyl)-benzamide; N-[1-(3,5-Dimethyl-isoxazole-4-sulfonyl)-5-phenyl-4,5,6,7-tetrahydro-1H-benzoimidazol-5-ylmethyl]-2-methoxy-benzamide; N-[3-(3,5-Dimethyl-isoxazole-4-sulfonyl)-5-phenyl-4,5,6,7-tetrahydro-3H-benzoimidazol-5-ylmethyl]-2-methoxy-benzamide; N-[3-(5-Chloro-3-methyl-1H-pyrazole-4-sulfonyl)-5-phenyl-4,5,6,7-tetrahydro-3H-benzoimidazol-5-ylmethyl]-2-ethoxy-benzamide; N-[1-(5-Chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl)-5-phenyl-4,5,6,7-tetrahydro-1H-benzoimidazol-5-ylmethyl]-2-methoxy-benzamide; N-(2-Amino-6-phenyl-4,5,6,7-tetrahydro-benzothiazol-6-ylmethyl)-2-methoxy-benzamide; N-(2-Acetylamino-6-phenyl-4,5,6,7-tetrahydro-benzothiazol-6-ylmethyl)-2-methoxy-benzamide; N-(2-Diacetylamino-6-phenyl-4,5,6,7-tetrahydro-benzothiazol-6-ylmethyl)-2-methoxy-benzamide; 2-Methoxy-N-(3-methyl-5-phenyl-4,5,6,7-tetrahydro-1H-indazol-5-ylmethyl)-benzamide; 2-Methoxy-N-(3-methyl-5-phenyl-4,5,6,7-tetrahydro-benzo[d]isoxazol-5-ylmethyl)-benzamide; 2-Methoxy-N-(3-methyl-5-phenyl-4,5,6,7-tetrahydro-benzo [c]isoxazol-5-ylmethyl)-benzamide; 2-Methoxy-N-(3-oxo-5-phenyl-2,3,4,5,6,7-hexahydro-1H-indazol-5-ylmethyl)-benzamide; 2-Methoxy-N-(3-oxo-5-phenyl-1,3,4,5,6,7-hexahydro-benzo[c]isoxazol-5-ylmethyl)-benzamide; 2-Methoxy-N-(1-methyl-3-oxo-5-phenyl-1,3,4,5,6,7-hexahydro-benzo[c]isoxazol-5-ylmethyl)-benzamide; 2-Methoxy-N-(6-phenyl-4,5,6,7-tetrahydro-benzo[1,2,3]thiadiazol-6-ylmethyl)-benzamide; 2-Methoxy-N-(6-phenyl-4,5,6,7-tetrahydro-1H-indazol-6-ylmethyl)-benzamide; 2-Methoxy-N-(2-methyl-6-phenyl-4,5,6,7-tetrahydro-2H-indazol-6-ylmethyl)-benzamide; 2-Methoxy-N-(6-phenyl-4,5,6,7-tetrahydro-benzo[d]isoxazol-6-ylmethyl)-benzamide; 2-Methoxy-N-(6-phenyl-4,5,6,7-tetrahydro-benzo[c]isoxazol-6-ylmethyl)-benzamide; 2-Methoxy-N-(3-phenyl-2,3,4,9-tetrahydro-1H-carbazol-3-ylmethyl)-benzamide; 2-Methoxy-N-(9-methyl-3-phenyl-2,3,4,9-tetrahydro-1H-carbazol-3-ylmethyl)-benzamide; 2-Methoxy-N-(((6S,7aS)-3-methoxy-6-phenyl-3a,4,5,6,7,7a-hexahydrobenzo[d]isoxazol-6-yl)methyl)benzamide; 2-Methoxy-N-(((3aS,5S)-3-methoxy-5-phenyl-3a,4,5,6,7,7a-hexahydrobenzo[d]isoxazol-5-yl)methyl)benzamide; 2-Methoxy-N-(((3aS,5R)-3-methoxy-5-phenyl-3a,4,5,6,7,7a-hexahydrobenzo[d]isoxazol-5-yl)methyl)benzamide; or 2-Methoxy-N-(((6R,7aS)-3-methoxy-6-phenyl-3a,4,5,6,7,7a-hexahydrobenzo[d]isoxazol-6-yl)methyl)benzamide.
 11. A compound of claim 1, selected from: N-(2-Amino-6-phenyl-5,6,7,8-tetrahydro-quinazolin-6-ylmethyl)-2-methoxy-benzamide; 2-Methoxy-N-(2-methyl-6-phenyl-5,6,7,8-tetrahydro-quinazolin-6-ylmethyl)-benzamide; N-(2-tert-Butyl-6-phenyl-5,6,7,8-tetrahydro-quinazolin-6-ylmethyl)-2-methoxy-benzamide; 2-Methoxy-N-(2-methylsulfanyl-6-phenyl-5,6,7,8-tetrahydro-quinazolin-6-ylmethyl)-benzamide; 2-Methoxy-N-(2-methoxy-6-phenyl-5,6,7,8-tetrahydro-quinazolin-6-ylmethyl)-benzamide; 2-Methoxy-N-(6-phenyl-5,6,7,8-tetrahydro-quinazolin-6-ylmethyl)-benzamide; N-(2-Dimethylamino-6-phenyl-5,6,7,8-tetrahydro-quinazolin-6-ylmethyl)-2-methoxy-benzamide (enantiomer 1); N-(2-Dimethylamino-6-phenyl-5,6,7,8-tetrahydro-quinazolin-6-ylmethyl)-2-methoxy-benzamide (enantiomer 2); 2-Methoxy-N-(2-methylamino-6-phenyl-5,6,7,8-tetrahydro-quinazolin-6-ylmethyl)-benzamide (enantiomer 1); 2-Methoxy-N-(2-methylamino-6-phenyl-5,6,7,8-tetrahydro-quinazolin-6-ylmethyl)-benzamide (enantiomer 2); N-(2-Ethylamino-6-phenyl-5,6,7,8-tetrahydro-quinazolin-6-ylmethyl)-2-methoxy-benzamide (enantiomer 1); N-(2-Ethylamino-6-phenyl-5,6,7,8-tetrahydro-quinazolin-6-ylmethyl)-2-methoxy-benzamide (enantiomer 2); 2-Methoxy-N-(2-morpholin-4-yl-6-phenyl-5,6,7,8-tetrahydro-quinazolin-6-ylmethyl)-benzamide (enantiomer 1); 2-Methoxy-N-(2-morpholin-4-yl-6-phenyl-5,6,7,8-tetrahydro-quinazolin-6-ylmethyl)-benzamide (enantiomer 2); N-(2-Dimethylamino-4-methyl-6-phenyl-5,6,7,8-tetrahydro-quinazolin-6-ylmethyl)-2-methoxy-benzamide; N-(2-Dimethylamino-4-oxo-6-phenyl-3,4,5,6,7,8-hexahydro-quinazolin-6-ylmethyl)-2-methoxy-benzamide; or 2-Methoxy-N-(6-phenyl-5,6,7,8-tetrahydro-quinolin-6-ylmethyl)-benzamide.
 12. A method of treating or preventing arrhythmias comprising administering to a patient in need thereof an effective amount of at least one compound of claim
 1. 13. A method of treating or preventing atrial fibrillation comprising administering to a patient in need thereof an effective amount of at least one compound of claim
 1. 14. A method of treating or preventing atrial flutter comprising administering to a patient in need thereof an effective amount of at least one compound of claim
 1. 15. A method of selectively treating or preventing supraventricular arrhythmias comprising administering to a patient in need thereof an effective amount of at least one compound of claim
 1. 16. A method of controlling heart rate comprising administering to a patient in need thereof an effective amount of at least one compound of claim
 1. 17. A method of treating gastrointestinal disorders comprising administering to a patient in need thereof an effective amount of at least one compound of claim
 1. 18. The method of claim 17, wherein the gastrointestinal disorder is reflux esauphagitis or a motility disorder.
 19. A method of treating inflammatory or immunological disease comprising administering to a patient in need thereof an effective amount of at least one compound of claim
 1. 20. The method of claim 19, wherein the disease is chronic obstructive pulmonary disease.
 21. A method of treating diabetes, a cognitive disorder, migraine, epilepsy or hypertension comprising administering to a patient in need thereof an effective amount of at least one compound of claim
 1. 22. A method of treating I_(Kur)-associated conditions comprising administering to a patient in need thereof an effective amount of at least one compound of claim
 1. 23. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 1 and a pharmaceutically acceptable vehicle or carrier thereof.
 24. The pharmaceutical composition of claim 23, further comprising at least one other therapeutic agent.
 25. The pharmaceutical composition of claim 24, wherein the other therapeutic agent is an anti-arrhythmic agent, a calcium channel blocker, an anti-platelet agent, an anti-hypertensive agent, an anti thrombotic/anti thrombolytic agent, an anti coagulant, an HMG-CoA reductase inhibitor, an anti diabetic agent, a thyroid mimetic, a mineralocorticoid receptor antagonist, or a cardiac glycoside.
 26. A pharmaceutical composition or kit comprising a pharmaceutical composition of claim 23 and a therapeutically effective amount of propafenone, carvadiol, propranolol, sotalol, dofetilide, amiodarone, azimilide, ibutilide, diltiazem, verapamil, sulamserod, serraline, tropsetron, dronedarone, diltiazem, verapamil, nifedipine, amlodipine, mybefradil, aspirin, indomethacin, ibuprofen, piroxicam, naproxen, celebrex, vioxx, abciximab, eptifibatide, tirofiban, clopidogrel, cangrelor, ticlopidine, CS-747, ifetroban, aspirin, dipyridamole, chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid, tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone, captropril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril, losartan, irbesartan, valsartan, sitaxsentan, atrsentan, omapatrilat, gemopatrilat, nitrates, tPA, recombinant tPA, tenecteplase (TNK), lanoteplase (nPA), razaxaban, hirudin, argatroban, streptokinase, urokinase, prourokinase, anisoylated plasminogen streptokinase activator complex, warfarin, heparins (including unfractionated, low molecular weight heparins such as enoxaparin, dalteparin), pravastatin lovastatin, atorvastatin, simvastatin, NK-104, ZD-4522, squalene, questran, cyclosporin A, taxol, FK 506, adriamycin, taxol, adriamycin, epothilones, cisplatin, carboplatin, metformin, acarbose, insulins, repaglinide, glimepiride, glyburide, glipizide, biguanide/glyburide combinations, troglitazone, rosiglitazone, pioglitazone, PPAR-gamma agonists, aP2 inhibitors, thyrotropin, polythyroid, KB-130015, dronedarone, spironolactone, eplerinone, alendronate, raloxifene, estrogen (including conjugated estrogens in premarin, estradiol), nefazodone, sertraline, diazepam, lorazepam, buspirone, hydroxyzine pamoate, famotidine, ranitidine, omeprazole, orlistat, digitalis, ouabain, cilostazol, sildenafil, prednisone, dexamethasone, or enbrel.
 27. A method of synthesizing a compound of formula I according to claim 1, comprising cyclizing a compound of formula II:

wherein J is oxo or —OZ* where Z* is a leaving group; via one or more ring-forming reactions to provide a compound according to formula I. 